Benzotriazoles anti-inflammatory compounds

ABSTRACT

The present invention relates to novel benzotriazoles of the formula I                    
     wherein Het is an optionally substituted 5-membered heterocycle containing one to two heteroatoms selected from nitrogen, sulfur and oxygen wherein at least one of said heteroatoms atoms must be nitrogen; 
     R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl or other suitable substituents; 
     R 3  is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl or other suitable substituents; 
     s is an integer from 0-5; 
     to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention are potent inhibitors of MAP kinases, preferably p38 kinase. They are useful in the treatment of inflammation, osteoarthritis, rheumatoid arthritis, cancer, repurfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.

The present invention relates to novel benzotriazoles, to intermediatesfor their preparation, to pharmaceutical compositions containing themand to their medicinal use. The compounds of the present invention arepotent inhibitors of MAP kinases, preferably p38 kinase. They are usefulin the treatment of inflammation, osteoarthritis, rheumatoid arthritis,cancer, reperfusion or ischemia in stroke or heart attack, autoimmunediseases and other disorders.

Intracellular signal transduction is the means by which cells respond toextracellular stimuli. Regardless of the nature of the cell surfacereceptor (e.g. protein tyrosine kinase or seven-transmembrane G-proteincoupled), protein kinases and phosphatases along with phospholipases arethe essential machinery by which the signal is further transmittedwithin the cell [Marshall, J. C. Cell, 80, 179-278 (1995)]. Proteinkinases can be categorized into five classes with the two major classesbeing, tyrosine kinases and serine/threonine kinases depending uponwhether the enzyme phosphorylates its substrate(s) on specifictyrosine(s) or serine/threonine(s) residues [Hunter, T. Methods inEnzymology (Protein Kinase Classification) p. 3, Hunter, T.; Sefton, B.M.; eds. vol. 200, Academic Press; San Diego, 1991].

For most biological responses, multiple intracellular kinases areinvolved and an individual kinase can be involved in more than onesignaling pathway. These kinases are often cytosolic and can translocateto the nucleus or the ribosomes where they can affect transcriptionaland translational events, respectively. The involvement of kinases intranscriptional control is presently much better understood than theireffect on translation as illustrated by the studies on growth factorinduced signal transduction involving MAP/ERK kinase [Marshall, C. J.Cell, 80, 179 (1995); Herskowitz, I. Cell 80, 187 (1995); Hunter, T.Cell, 80, 225 (1995); Seger, R., and Krebs, E. G. FASEB J., 726-735(1995)].

While many signaling pathways are part of normal cell homeostasis,numerous cytokines (e.g., IL-1 and TNF) and certain other mediators ofinflammation (e.g., COX-2, and iNOS) are produced only as a response tostress signals such as bacterial lipopolysaccharide (LPS). Earlyevidence suggesting that the signal transduction pathway leading toLPS-induced cytokine biosynthesis involved protein kinases came fromstudies of Weinstein [Weinstein, et al., J. Immunol 151, 3829(1993)] butthe specific protein kinases involved were not identified. Working froma similar perspective, Han [Han, et al., Science 265, 808(1994)]identified murine p38 as a kinase which is tyrosine phosphorylated inresponse to LPS. Additional evidence of the involvement of the p38kinase in LPS-stimulated signal transduction pathway leading to theinitiation of proinflammatory cytokine biosynthesis was provided by thediscovery of p38 kinase (CSBP 1 and 2) by Lee [Lee; et al, Nature, 372,739(1994)] as the molecular target for a novel class ofanti-inflammatory agents. Thus, compounds that inhibit p38 will inhibitIL-1 and TNF synthesis in human monocytes. Such results have beenreported by [Lee, et al., Int. J. Immunopharmac. 10(7), 835(1988)] and[Lee; et al., Annals N.Y. Acad. Sci., 696, 149(1993)].

It is now accepted that CSBP/p38 is a one of several kinases involved ina stress-response signal transduction pathway which is parallel to andlargely independent of the analogous mitogen-activated protein kinase(MAP) kinase cascade (FIG. 1). Stress signals, including LPS,pro-inflammatory cytokines, oxidants, UV light and osmotic stress,activate kinases upstream from CSBP/p38 which in turn phosphorylateCSBP/p38 at threonine 180 and tyrosine 182 resulting in CSBP/p38activation. MAPKAP kinase-2 and MAPKAP kinase-3 have been identified asdownstream substrates of CSBP/p38 which in turn phosphorylate heat shockprotein Hsp 27. It is now known that MAPKAP-2 is essential for LPSinduced TNFα biosynthesis [Kotlyarov et al. Nature Cell Biol., 1, 94(1999), see also Cohen, P. Trends Cell Biol. 353-361(1997)].

In addition to inhibiting IL-1 and TNF, CSBP/p38 kinase inhibitors alsodecrease the synthesis of a wide variety of pro-inflammatory proteinsincluding, IL-6, IL-8, GM-CSF and COX-2. Inhibitors of CSBP/p38 kinasehave also been shown to suppress the TNF-induced expression of VCAM-1 onendothelial cells, the TNF-induced phosphorylation and activation ofcytosolic PLA2 and the IL-1 stimulated synthesis of collagenase andstromelysin. These and additional data demonstrate that CSBP/p38 isinvolved not only cytokine synthesis, but also in cytokine signaling[CSBP/p38 kinase reviewed in Cohen, P. Trends Cell Biol., 353-361(1997)].

Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biologicalsubstances produced by a variety of cells, such as monocytes ormacrophages. IL-1 has been demonstrated to mediate a variety ofbiological activities thought to be important in immunoregulation andother physiological conditions such as inflammation [See, e.g, Dinarelloet al., Rev. Infect. Disease, 6, 51 (1984)]. The myriad of knownbiological activities of IL-1 include the activation of T helper cells,induction of fever, stimulation of prostaglandin or collagenaseproduction, neutrophil chemotaxis, induction of acute phase proteins andthe suppression of plasma iron levels.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These disease states include rheumatoid arthritis, osteoarthritis,endotoxemia and/or toxic shock syndrome, other acute or chronicinflammatory disease states such as the inflammatory reaction induced byendotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis,muscle degeneration, cachexia, psoriatic arthritis and Reiter'ssyndrome; gout, traumatic arthritis, rubella arthritis, and acutesynovitis. Recent evidence also links IL-1 activity to diabetes andpancreatic β cell disfunction, Dinarello, J. Clinical Immunology, 5 (5),287-297 (1985).

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions; sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusioninjury, graft vs. host reaction, allograft rejections, fever andmyalgias due to infection, such as influenza, cachexia secondary toinfection or malignancy, cachexia secondary to acquired immunedeficiency syndrome (AIDS), AIDS, or ARC (AIDS related complex), keloidinformation, scar tissue formation, Crohn's disease, ulcerative colitis,or pyrosis.

Interleukin-8 (IL-8) is a chemotactic factor produced by several celltypes including mononuclear cells, fibroblasts, endothelial cells, andkeratinocytes. Its production from endothelial cells is induced by IL-1,TNF, or lipopolysaccharide (LPS). IL-8 stimulates a number of functionsin vitro. It has been shown to have chemoattractant properties forneutrophils, T-lymphocytes, and basophils. In addition it induceshistamine release from basophils from both normal and atopic individualsas well lysozomal enzyme release and respiratory burst from neutrophils.IL-8 has also been shown to increase the surface expression of Mac-1(CD11b/CD18) on neutrophils without de novo protein synthesis, this maycontribute to increased adhesion of the neutrophils to vascularendothelial cells. Many diseases are characterized by massive neutrophilinfiltration. Conditions associated with an increase in IL-8 production(which is responsible for chemotaxis of neutrophils into theinflammatory site) would benefit by compounds, which are suppressive ofIL-8 production.

IL-1 and TNF affect a wide variety of cells and tissues and thesecytokines as well as other leukocyte-derived cytokines are important andcritical inflammatory mediators of a wide variety of disease states andconditions. The inhibition of these cytokines is of benefit incontrolling, reducing and alleviating many of these disease states.

Inhibition of signal transduction via CSBP/p38, which in addition toIL-1, TNF and IL-8 described above is also required for the synthesisand/or action of several additional pro-inflammatory proteins (i.e.,IL-6, GM-CSF, COX-2, collagenase and stromelysin), is expected to be ahighly effective mechanism for regulating the excessive and destructiveactivation of the immune system. This expectation is supported by thepotent and diverse anti-inflammatory activities described for CSBP/p38kinase inhibitors [Badger, et al., J. Pharm. Exp. Thera. 279 (3);1453-1461. (1996); Griswold, et al., Pharmacol. Comm., 7, 323-229(1996)].

There remains a need for treatment, in this field, for compounds, whichare cytokine suppressive anti-inflammatory drugs, i.e., compounds thatare capable of inhibiting the CSBP/p38/RK kinase.

CSBP/p38/RK kinase inhibitors are well known to those skilled in theart. International Patent Publication WO 00/40243, published Jul. 13,2000, refers to pyridine substituted pyridine compounds and states thatthese compounds are p38 inhibitors. International Patent Publication WO00/63204, published Oct. 26, 2000, refers to substituted azole compoundsand states that these compounds are p38 inhibitors. International PatentPublication WO 00/31065, published Jun. 2, 2000, refers to certainheterocyclic compounds and states that these compounds are p38inhibitors. International Patent Publication WO 00/06563, published Feb.10, 2000, refers to substituted imidazole compounds and states thatthese compounds are p38 inhibitors. International Patent Publication WO00/41698, published Jul. 20, 2000, refers to certain ω-carboxy arylsubstituted diphenyl urea compounds and states that these compounds arep38 inhibitors. U.S. Pat. No. 5,716,955 refers to certain substitutedimidazole compounds and states that these compounds are p38 inhibitors.U.S. Pat. No. 5,716,972 refers to certain pyridinyl substitutedimidazole compounds and states that these compounds are p38 inhibitors.U.S. Pat. No. 5,717,100 refers to certain pyridinyl substitutedimidazole compounds and states that these compounds are p38 inhibitors.U.S. Pat. No. 5,756,499 refers to certain substituted imidazolecompounds and states that these compounds are p38 inhibitors. U.S.Provisional Application Nos. 60/274,791 and 60/274,840, both filed Mar.9, 2001, refer to benzimidazolone and triazolopyridine p38 inhibitors,respectively.

SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula

wherein Het is an optionally substituted 5-membered heteroarylcontaining one or two heteroatoms selected from nitrogen, sulfur andoxygen wherein at least one of said heteroatoms atoms must be nitrogen;

R² is selected from the group consisting of hydrogen, (C₁-C₆)alkyl orother suitable substituents;

R³ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl orother suitable substituents; and

s is an integer from zero to five;

and pharmaceutically acceptable salts and prodrugs thereof.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula 1. The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the chloride, bromide, iodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate,citrate, acid citrate, tartrate, bitartrate, succinate, maleate,fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

The invention also relates to base addition salts of formula I. Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula I that are acidic innature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (e.g., potassium and sodium) and alkaline earth metal cations(e.g., calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine-(meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

The compounds of this invention include all stereoisomers (e.g., cis andtrans isomers) and all optical isomers of compounds of the formula I(e.g., R and S enantiomers), as well as racemic, diastereomeric andother mixtures of such isomers.

The compounds, salts and prodrugs of the present invention can exist inseveral tautomeric forms, including the enol and imine form, and theketo and enamine form and geometric isomers and mixtures thereof. Allsuch tautomeric forms are included within the scope of the presentinvention. Tautomers exist as mixtures of a tautomeric set in solution.In solid form, usually one tautomer predominates. Even though onetautomer may be described, the present invention includes all tautomersof the present compounds.

The present invention also includes atropisomers of the presentinvention. Atropisomers refer to compounds of formula I that can beseparated into rotationally restricted isomers.

The compounds of this invention may contain olefin-like double bonds.When such bonds are present, the compounds of the invention exist as cisand trans configurations and as mixtures thereof.

A “suitable substituent” is intended to mean a chemically andpharmaceutically acceptable functional group i.e., a moiety that doesnot negate the inhibitory activity of the inventive compounds. Suchsuitable substituents may be routinely selected by those skilled in theart. Illustrative examples of suitable substituents include, but are notlimited to halo groups, perfluoroalkyl groups, perfluoroalkoxy groups,alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups, oxogroups, mercapto groups, alkylthio groups, alkoxy groups, aryl orheteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl orheteroaralkyl groups, aralkoxy or heteroaralkoxy groups, HO—(C═O)—groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups,alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groupsdialkylamino carbonyl groups, arylcarbonyl groups, aryloxycarbonylgroups, alkylsulfonyl groups, arylsulfonyl groups and the like. Thoseskilled in the art will appreciate that many substituents can besubstituted by additional substituents.

More specifically, the present invention also relates to a compound ofthe formula

wherein Het is an optionally substituted 5-membered heteroaryl whichtaken together with (R³—)_(s) phenyl is selected from the groupconsisting of

R² is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, phenyl, (C₁-C₁₀)heteroaryl and (C₁-C₁₀)heterocyclic;wherein each of the aforesaid (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, phenyl,(C₁-C₁₀)heteroaryl and (C₁-C₁₀)heterocyclic substituents may optionallybe independently substituted by one to four moieties independentlyselected from the group consisting of halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, phenyl,(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, formyl,—CN, (C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,phenyl-NH—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, H₂N—(C═O)—NH—,(C₁-C₆)alkyl-HN—(C═O)—NH—, [(C₁-C₆)alkyl-]₂N—(C═O)—NH—,(C₁-C₆)alkyl-HN—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₁-C₆)alkyl-]₂N—(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-HN—(C═O)—NH—,(phenyl-)₂N—(C═O)—NH—, phenyl-HN—(C═O)—[((C₁-C₆)alkyl)—N]—,(phenyl-)₂N—(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₆)alkyl-O—(C═O)—NH—,(C₁-C₆)alkyl-O—(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-O—(C═O)—NH—,phenyl-O—(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₆)alkyl-SO₂NH—, phenyl-SO₂NH—,(C₁-C₆)alkyl-SO₂—, phenyl-SO₂—, hydroxy, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, phenoxy, (C₁-C₆)alkyl-(C═O)—O—, phenyl-(C═O)—O—,H₂N—(C═O)—O—, (C₁-C₆)alkyl-HN—(C═O)—O—, [(C₁-C₆)alkyl-]₂N—(C═O)—O—,phenyl-HN—(C═O)—O—, and (phenyl-)₂N—(C═O)—O—; wherein two adjacent R²substituents on said (C₃-C₁₀)cycloalkyl, phenyl, (C₁-C₁₀)heteroaryl or(C₁-C₁₀)heterocyclic may be taken together with the carbon or heteroatomto which they are attached to form a five to six membered carbocyclic orheterocyclic ring; wherein each of said moieties containing a phenylalternative may optionally be substituted by one or two radicalsindependently selected from the group consisting of (C₁-C₆)alkyl, halo,(C₁-C₆)alkoxy, (C₁-C₆)alkyl and perhalo(C₁-C₆)alkoxy;

each R³ is independently selected from the group consisting of halo,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl,hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy,(C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—,(C₁-C₆)alkyl-S, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—NH—, phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN,(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)— and(C₁-C₆)alkyl-(C═O)—O—; wherein two adjacent R³ substituents mayoptionally be taken together to form a three to six membered carbocyclicor heterocyclic ring;

s is an integer from zero to five;

R⁴ and R⁵ are each independently selected from the group consisting ofhydrogen, halo and R⁹—B—(CH₂)_(n)—;

n is an integer from zero to six;

each B is independently a bond, —(CHR¹⁰)—, —O—, —S—, —(SO₂)—, —(C═)—,—O(C═)—, —(C═O)—O—, —(C═O)—NR¹⁰—, —(R¹⁰—N)—, —(R¹⁰—N)—SO₂—,—(R¹⁰—N)—(C═)—, —SO₂—(NR¹⁰)—, —(R¹⁰—N)—(C═O)—(NR¹⁰)—, —(O)—(C═O)—(NR¹⁰)—or —(R¹⁰—N)—(C═O)—O—;

R⁵ and R⁷ are each independently selected from the group consisting ofhydrogen, R¹⁴—(CR¹⁵H)_(p)—, phenyl, (C₁-C₁₀)heteroaryl,(C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl-(SO₂)—,phenyl-(SO₂)—, H₂N—(SO₂)—, (C₁-C₆)alkyl-NH—(SO₂)—,[(C₁-C₆)alkyl-]₂N—(SO₂)—, phenyl-NH—(SO₂)—, (phenyl-)₂N—(SO₂)—,R¹⁶—(C₁-C₆)alkyl-(C═O)—, phenyl-(C═)—, (C₁-C₁₀)heteroaryl-(C═)—,(C₁-C₁₀)heterocyclic-(C═)—, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═)—, H₂N—(C═)—, (C₁-C₆)alkyl-NH—(C═)—,phenyl-NH—(C═)—, (C₁-C₁₀)heteroaryl-NH—(C═)—,(C₁-C₁₀)heterocyclic-NH—(C═)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,[(C₁-C₆)alkyl-]₂N—(C═O)—, (phenyl-)₂N—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heteroaryl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heterocyclic-[((C₁-C₆)alkyl)—N]—(C═)—, and(C₃-C₁₀)cycloalkyl-[((C₁-C₆)alkyl)—N]—(C═)—, wherein each of theaforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R⁵ and R⁷alternatives may optionally be independently substituted by one to fourmoieties independently selected from the group consisting of halo,R¹⁶—(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, phenyl, benzyl, (C₁-C₁₀)heterocyclic,(C₁-C₁₀)heteroaryl, (C₁-C₆)alkyl-SO₂—, formyl, —CN, (C₁-C₆)alkyl-(C═)—,(C₃-C₁₀)cycloalkyl-(C═)—, phenyl-(C═)—, (C₁-C₁₀)heterocyclic-(C═)—,(C₁-C₁₀)heteroaryl-(C═)—, HO—(C═)—, (C₁-C₆)alkyl-O—(C═)—,(C₃-C₁₀)cycloalkyl-O—(C═)—, (C₁-C₁₀)heterocyclic-O—(C═)—,(C₁-C₆)alkyl-NH—(C═)—, (C₃-C₁₀)cycloalkyl-NH—(C═)—, phenyl-NH—(C═)—,(C₁-C₁₀)heterocyclic-NH—(C═)—, (C₁-C₁₀)heteroaryl-NH—(C═)—,[(C₁-C₆)alkyl]₂—N—(C═)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—, (C₁-C₆)alkyl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—, phenyl-(C═O)—NH—,(C₁-C₁₀)heterocyclic-(C═O)—NH—, (C₁-C₁₀)heteroaryl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—[(C₁-C₆)alkyl-N]—,(C₁-C₆)alkyl-SO₂NH—, (C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—,(C₁-C₁₀)heterocyclic-SO₂NH— and (C₁-C₁₀)heteroaryl-SO₂NH—; wherein eachof said phenyl and heteroaryl moiety alternatives may optionally besubstituted by one or two radicals independently selected from halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, perfluoro(C₁-C₆)alkyl andperfluoro(C₁-C₆)alkoxy;

p is an integer from one to six;

R⁹ is selected from the group consisting of hydrogen, —CF₃, —C═N,R¹³—(R¹²CH)_(m)—, phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic and(C₃-C₁₀)cycloalkyl; wherein each of the aforesaid R⁹ phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkylsubstituents may optionally be substituted by one to four moietiesindependently selected from the group consisting of halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy, (C₁-C₁₀)heteroaryl-O—,(C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—; wherein two adjacent moietieson said R⁹ phenyl, (C₁-C₁₀)heterocyclic or (C₃-C₁₀)cycloalkylsubstituents may be taken together with the carbon or heteroatom towhich they are attached to form a five to six membered heterocyclic orcarbocyclic ring;

m is an integer from one to six;

R¹⁰ is hydrogen, (C₁-C₆)alkyl-SO₂— or (C₁-C₆)alkyl;

R¹¹ is hydrogen or (C₁-C₆)alkyl;

each R¹² is independently selected from the group consisting ofhydrogen, amino, (C₁-C₆)alkoxy or (C₁-C₆)alkyl;

R¹³ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl, (C₁-C₁₀)heteroaryl,(C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, phenoxy, (C₁-C₁₀)heteroaryl-O—,(C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, phenyl-SO₂—NH—,(C₁-C₆)alkyl-SO₂—[((C₁-C₆)alkyl)—N]—, phenyl-SO₂—[((C₁-C₆)alkyl)—N]—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—NH—, phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN,(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—;

R¹⁴ is selected from the group consisting of hydrogen, halo,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, phenyl, (C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl,phenyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, phenyl-SO₂—, H₂N—SO₂—,(C₁-C₆)alkyl-NH—SO₂—, phenyl-NH—SO₂—, [(C₁-C₆)alkyl-]₂N—SO₂—,(phenyl-)₂N—SO₂—, formyl, —CN, (C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, R¹⁶—(C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—, H₂N—(C═O)—,R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,phenyl-NH—(C═O)—, (C₁-C₁₀)heterocyclic-NH—(C═O)—,(C₁-C₁₀)heteroaryl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heteroaryl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heterocyclic-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₃-C₁₀)cycloalkyl[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy, R¹⁶—(C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—,R¹⁶—(C₁-C₆)alkyl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,R⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,R⁶—(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,phenyl-(C═O)—NH—, (C₁-C₁₀)heterocyclic-(C═O)—NH—,(C₁-C₁₀)heteroaryl-(C═O)—NH—,R¹⁶—(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, R⁶—(C₁-C₆)alkyl-SO₂NH—,(C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH—and (C₁-C₁₀)heteroaryl-SO₂NH—; wherein each of the aforesaid phenyl,heterocyclic, heteroaryl or cycloalkyl R¹⁴ alternatives may optionallybe independently substituted by one to four moieties independentlyselected from the group consisting of halo, R¹⁶—(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,phenyl, benzyl, (C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl,(C₁-C₆)alkyl-SO₂—, formyl, —CN, R¹⁶—(C₁-C₆)alkyl-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₁₀)heteroaryl-O—(C═O)—, H₂N—(C═O)—, R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy,R¹⁶—(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—,R¹⁶—(C₁-C₆)alkyl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,R¹⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,phenyl-(C═O)—NH—, (C₁-C₁₀)heterocyclic-(C═O)—NH—,(C₁-C₁₀)heteroaryl-(C═O)—NH—,R¹⁶—(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, R¹⁶-(C₁-C₆)alkyl-SO₂NH—,(C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH—and (C₁-C₁₀)heteroaryl-SO₂NH—; wherein each of said phenyl andheteroaryl moiety alternatives may optionally be substituted by one ortwo radicals independently selected from the group consisting of halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, perfluoro(C₁-C₆)alkyl andperfluoro(C₁-C₆)alkoxy;

each R¹⁵ is independently selected from the group consisting ofhydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, perhalo(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—O—,amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl and(C₁-C₆)alkyl-(C═O)—NH—;

each R¹⁶ is independently selected from the group consisting ofhydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,perhalo(C₁-C₆)alkyl, (C₁-C₁₀)heterocyclic, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,(C₁-C₆)alkyl-(C═O)—O—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, formamidyl and (C₁-C₆)alkyl-(C═O)—NH—; whereinsaid (C₁-C₁₀)heterocyclic may optionally be substituted by one to threesubstituents independently selected from the group consisting of halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino and[(C₁-C₆)alkyl]₂-amino;

or R⁴ and R⁶ or R⁴ and R⁷ or R⁵ and R⁶ may be taken together with theatoms to which they are attached to form an optionally substituted fiveto ten membered saturated, unsaturated or aromatic ring optionallycontaining two to three heteroatoms independently selected from NH, N,O, S, SO or SO₂; wherein said ring may be optionally substituted by oneto three substituents independently selected from the group consistingof oxo, halo, (C₁-C₆)alkyl, phenyl, (C₁-C₁₀)heteroaryl,(C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy,phenoxy, (C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—,(C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—, phenyl-S—,phenyl-(S═O)—, phenyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—,[(C₁-C₆)alkyl]₂—N—SO₂—, phenyl-NH—SO₂—, (phenyl)₂—N—SO₂—,phenyl-[N(C₁-C₆)alkyl]-SO₂—, formyl, (C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₁-C₁₀)heterocyclic-O—(C═O)—, (C₃-C₁₀)cycloalkyl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[(C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heteroaryl-[(C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—,(C₁-C₁₀)heterocyclic-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-[((C₁-C₆)alkyl)—N]—(C═O)—, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-SO₂—NH—, phenyl-SO₂—NH—,(C₁-C₆)alkyl-SO₂—[((C₁-C₆)alkyl)—N]—, phenyl-SO₂—[((C₁-C₆)alkyl)—N]—,formamidyl, (C₁-C₆)alkyl-(C═O)—NH—,(C-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₁₀)heteroaryl-(C═O)—NH—,(C₁-C₁₀)heteroaryl-(C═O)—[((C₁-C₆)alkyl)—N]—,(C₁-C₁₀)heterocyclic-(C═O)—NH—,(C₁-C₁₀)heterocyclic-(C═O)—[((C₁-C₆)alkyl)—N]—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, H₂N(C═O)—NH—,(C₁-C₆)alkyl-HN—(C═O)—NH—, (C₁-C₆)alkyl-HN—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₁-C₆)alkyl]₂—N—(C═O)—NH—,[(C₁-C₆)alkyl]₂—N—(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-HN—(C═O)—NH—,phenyl-HN—(C═O)—[((C₁-C₆)alkyl)—N]—, (phenyl)₂—N—(C═O)—NH—,(phenyl)₂—N—(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₁₀)heteroaryl-HN—(C═O)—NH—,(C₁-C₁₀)heteroaryl-HN—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₁-C₁₀)heteroaryl]₂—N—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₁-C₁₀)heteroaryl]₂—N—(C═O)—NH—, (C₁-C₁₀)heterocyclic-HN—(C═O)—NH—,(C₁-C₁₀)heterocyclic-HN—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₁-C₁₀)heterocyclic]₂—N—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₁-C₁₀)heterocyclic]₂—N—(C═O)—NH—, (C₃-C₁₀)cycloalkyl-HN—(C═O)—NH—,(C₃-C₁₀)cycloalkyl-HN—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—O—,phenyl-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₆)alkyl-NH—(C═O)—O—, [(C₁-C₆)alkyl]₂—N—(C═O)—O—,phenyl-NH—(C═O)—O—, (C₁-C₁₀)heteroaryl-NH—(C═O)—O—,(C₁-C₁₀)heterocyclic-NH—(C═O)—O— and (C₃-C₁₀)cycloalkyl-NH—(C═O)—O—;

or the pharmaceutically acceptable salts thereof.

As used herein, the term “alkyl,” as well as the alkyl moieties of othergroups referred to herein (e.g., alkoxy), may be linear or branched(such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,secondary-butyl, tertiary-butyl); optionally substituted by 1 to 3suitable substituents as defined above such as fluoro, chloro,trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy or (C₁-C₆)alkyl. The phrase “each of said alkyl” as usedherein refers to any of the preceding alkyl moieties within a group suchalkoxy, alkenyl or alkylamino. Preferred alkyls include (C₁-C₄)alkyl,most preferably methyl and ethyl.

As used herein, the term “cycloalkyl” refers to a mono or bicycliccarbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl,cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl andbicyclo[5.2.0]nonanyl, etc.); optionally containing 1 or 2 double bondsand optionally substituted by 1 to 3 suitable substituents as definedabove such as fluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy,(C₆-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

As used herein, the term “halogen” includes fluoro, chloro, bromo oriodo or fluoride, chloride, bromide or iodide.

As used herein, the term “halo-substituted alkyl” refers to an alkylradical as described above substituted with one or more halogensincluded, but not limited to, chloromethyl, dichloromethyl,fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, andthe like; optionally substituted by 1 to 3 suitable substituents asdefined above such as fluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy,(C₆-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

As used herein, the term “alkenyl” means straight or branched chainunsaturated radicals of 2 to 6 carbon atoms, including, but not limitedto ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above such asfluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

As used herein, the term “(C₂-C₆)alkynyl” is used herein to meanstraight or branched hydrocarbon chain radicals having one triple bondincluding, but not limited to, ethynyl, propynyl, butynyl, and the like;optionally substituted by 1 to 3 suitable substituents as defined abovesuch as fluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

As used herein, the term “carbonyl” or “(C═O)” (as used in phrases suchas alkylcarbonyl, alkyl-(C═O)— or alkoxycarbonyl) refers to the joinderof the >C═O moiety to a second moiety such as an alkyl or amino group(i.e. an amido group). Alkoxycarbonylamino (i.e. alkoxy(C═O)—NH—) refersto an alkyl carbamate group. The carbonyl group is also equivalentlydefined herein as (C═O). Alkylcarbonylamino refers to groups such asacetamide.

As used herein, the term “phenyl-[(C₁-C₆)alkyl)—N]—(C═O)—,” as usedherein, refers to a disubstituted amide group of the formula

As used herein, the term “aryl” means aromatic radicals such as phenyl,naphthyl, tetrahydronaphthyl, indanyl and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above such asfluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

As used herein, the term “heteroaryl” refers to an aromatic heterocyclicgroup usually with one heteroatom selected from O, S and N in the ring.In addition to said heteroatom, the aromatic group may optionally haveup to four N atoms in the ring. For example, heteroaryl group includespyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl,imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl),thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl,triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g.,1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl,isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above such asfluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl. Particularlypreferred heteroaryl groups include oxazolyl, imidazolyl, pyridyl,thienyl, furyl, thiazolyl and pyrazolyl (these heteroaryls are mostpreferred of the R⁴, R⁵, R⁶ and R⁷ heteroaryls).

The term “heterocyclic” as used herein refers to a cyclic groupcontaining 1-9 carbon atoms and 1 to 4 hetero atoms selected from N, O,S or NR′. Examples of such rings include azetidinyl, tetrahydrofuranyl,imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl,thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl,tetrahydro-thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl,oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl,chromanyl, isochromanyl, benzoxazinyl, and the like. Examples of saidmonocyclic saturated or partially saturated ring systems aretetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl,imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl,piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1,3xazolidin-3-yl,isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,1,3-pyrazolidin-1-yl, thiomorpholin-yl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl,1,2,5-oxathiazin-4-yl and the like; optionally substituted by 1 to 3suitable substituents as defined above such as fluoro, chloro,trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy or (C₁-C₆)alkyl. Preferred heterocyclics includetetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl andmorpholinyl.

Alternative, as used herein refers to a substituent, group or moietywhich contains as any component of the substituent, group or moiety thedesignated functionality. Thus the phrase “each of the aforesaid phenyl,heterocyclic, heteroaryl or cycloalkyl R⁵ and R⁷ alternatives” refers tothe R⁵ and R⁷ substituents containing a phenyl, heterocyclic, heteroarylor cycloalkyl functionality. In the present example the identifiedphenyl, heterocyclic, heteroaryl or cycloalkyl R⁵ and R⁷ substituentsare R⁴—(CR¹⁵H)_(p)—, phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic,(C₃-C₁₀)cycloalkyl, phenyl-(SO₂)—, phenyl-NH—(SO₂)—, (phenyl-)₂N—(SO₂)—,R¹⁶—(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₁₀)heterocyclic-O—(C═O)—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,phenyl-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(phenyl-)₂N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heteroaryl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heterocyclic-[((C₁-C₆)alkyl)—N]—(C═O)—, and(C₃-C₁₀)cycloalkyl-[((C₁-C₆)alkyl)—N]—(C═O)—.

Embodiment as used herein refers to specific groupings of compounds oruses into discrete subgenera. Such subgenera may be cognizable accordingto one particular substituent such as a specific R² group. Othersubgenera are cognizable according to combinations of varioussubstituents, such as all compounds wherein R² is methyl and R⁴ is agroup of the formula R⁹—B—(CH₂)_(n)— and n is zero. The phrase “incombination with each of the aforementioned embodiments” refers tocombinations of the identified embodiment with each embodimentpreviously identified in the specification. Thus an embodiment ofcompounds wherein R² is methyl “in combination with each of theaforementioned embodiments” refers to additional embodiments comprisingcombinations of the R² methyl embodiment with each embodiment previouslyidentified in the specification.

A preferred embodiment of the present invention is that group ofcompounds of formula I wherein R² is (C₁-C₆)alkyl, more preferably(C₁-C₅)alkyl, more preferably (C₁-C₄)alkyl, more preferably methyl,ethyl, or isopropyl.

Another embodiment of the present invention is that group of compoundsof formula I, wherein R² is optionally substituted (C₃-C₆)cycloalkyl,more preferably optionally substituted cyclobutyl or cyclopentyl; morepreferably optionally substituted by 1 to 3 substituents selected fromthe group consisting of fluoro, chloro, trifluoromethyl, hydroxy,(C₁-C₆)alkoxy, amino, trifluoromethoxy, and (C₁-C₆)alkyl.

Another embodiment of the present invention is that group of compoundsof formula I wherein R² is optionally substituted phenyl; morepreferably optionally substituted by 1 to 3 substituents selected fromthe group consisting of fluoro, chloro, trifluoromethyl, hydroxy,(C₁-C₆)alkoxy, amino, trifluoromethoxy, and (C₁-C₆)alkyl.

Another embodiment of the present invention is that group of compoundsof formula I wherein R² is optionally substituted (C₁-C₁₀)heterocyclic,more preferably optionally substituted tetrahydrofuranyl, morepreferably optionally substituted by 1 to 2 substituents independentlyselected from the group consisting of fluoro, chloro, trifluoromethyl,hydroxy, (C₁-C₆)alkoxy, amino, trifluoromethoxy, and (C₁-C₆)alkyl.

Another embodiment of the present invention include that group ofcompounds of formula I wherein R² is optionally substituted(C₁-C₁₀)heteroaryl, more preferably optionally substituted thiophenyland pyridinyl, more preferably optionally substituted by 1 to 2substituents independently selected from the group consisting of fluoro,chloro, trifluoromethyl, hydroxy, (C₁-C₆)alkoxy, amino,trifluoromethoxy, and (C₁-C₆)alkyl.

Another embodiment of the present invention is that group of compoundsof formula I, wherein R² is hydrogen.

An embodiment of the present invention includes compounds of formula I,referred to as the phenyl-pyrolyl-benzotriazoles, wherein the compoundhas the formula

Other embodiments of the present invention include those compounds offormula I(a) in combination with each of the aforementioned embodimentsof R².

An embodiment of the present invention includes compounds of formula I,referred to as the phenyl-imidazolyl-benzotriazoles, wherein thecompound has the formula

Other embodiments of the present invention include those compounds offormula I(b) in combination with each of the aforementioned embodimentsof R².

Another embodiment of the present invention includes compounds offormula I, referred to as the phenyl-pyrazolyl-benzotriazoles, whereinthe compound has the formula

Other embodiments of the present invention include those compounds offormula I(c) in combination with each of the aforementioned embodimentsof R

Another embodiment of the present invention includes compounds offormula I, referred to as the phenyl-oxazolyl-benzotriazoles, whereinthe compound has the formula

Other embodiments of the present invention include those compounds offormula I(d) in combination with each of the aforementioned embodimentsof R².

Another embodiment of the present invention includes compounds offormula I, referred to as the phenyl-isoxazolyl-benzotriazoles, whereinthe compound has the formula

Other embodiments of the present invention include those compounds offormula I(e) in combination with each of the aforementioned embodimentsof R².

Another embodiment of the present invention, referred to as thephenyl-pyrazolyl-benzotriazoles, are those group of compounds of formulaI wherein the compound has the be formula

Other embodiments of the present invention include those compounds offormula I(f) in combination with each of the aforementioned embodimentsof R².

Another embodiment of the present invention, referred to as thephenyl-thiazolyl-benzotriazoles, are those group of compounds of formulaI wherein the compound has the formula

Other embodiments of the present invention include those compounds offormula I(g) in combination with each of the aforementioned embodimentsof R².

Another embodiment of the present invention, referred to as thephenyl-isothiazolyl-benzotriazoles, are those group of compounds offormula I wherein the compound has the formula

Other embodiments of the present invention include those compounds offormula I(h) in combination with each of the aforementioned embodimentsof R².

Another preferred embodiment of the present invention is that group ofcompounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴is hydrogen. Other embodiments of the present invention include thosecompounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴is hydrogen in combination with the aforementioned embodiments of R².

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴ isR⁹—B—(CH₂)_(n)— and n is zero. Other embodiments of the presentinvention include those compounds of formula I (and I(a), I(c), I(e),I(f), and I(h)) wherein R⁴ is R⁹—B—(CH₂)_(n)— and n is zero incombination with the aforementioned embodiments of R².

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴ isR⁹—B—(CH₂)_(n)— and n is an integer from one to six, more preferably oneto five. Other embodiments of the present invention include thosecompounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴is R⁹—B—(CH₂)_(n)— and n is one to six, preferably one to five, incombination with the aforementioned embodiments of R².

Another preferred embodiment of the present invention is that group ofcompounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴is R⁹—B—(CH₂)_(n)—; n is zero; B is a bond and R⁹ is R¹³—(R¹²CH)_(m)—.Other embodiments of the present invention include those compounds offormula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴ isR⁹—B—(CH₂)_(n)—, n is zero and R⁹ is R¹³—(R¹²CH)_(m)— in combinationwith the aforementioned embodiments of R². More preferred embodiments ofthe invention of formula I (and I(c), I(e) and I(f)) are those compoundswherein R⁴ is R⁹—B—(CH₂)_(n)—, n is zero, R⁹ is R¹³—(R²CH)_(m)—, m isone to six and R and R¹³ are each hydrogen.

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴ isR⁹—B—(CH₂)_(n)—; n is zero; B is —(C═O)—(R¹⁰—N)—, —(R¹⁰—N)—,—SO₂—(R¹⁰—N)—, —(R¹⁰—N)—(C═O)—(NR¹¹)— or —(R¹⁰—N)—(C═O)—O—; and R⁹ isselected from the group consisting of hydrogen and R¹³—(R¹²CH)_(m)—;more preferably wherein R⁹ is R¹³—(R²CH)_(m)—; m is 1 to 6; R¹⁰ ishydrogen or methyl; each R¹² is independently selected from the groupsconsisting of hydrogen or methyl; and R¹³ is selected from the groupconsisting of hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy, (C₁-C₁₀)heteroaryl-O—,(C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₆)alkyl-SO₂—NH—, phenyl-SO₂—NH—,(C₁-C₆)alkyl-SO₂—[((C₁-C₆)alkyl)—N]—, phenyl-SO₂—[((C₁-C₆)alkyl)—N]—,—CN, (C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₁₀)heteroaryl-NH—(C═O)—, (C₁-C₁₀)heterocyclic-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,H₂N(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,phenyl-NH—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—. Other embodiments of thepresent invention include those compounds of formula I (and I(a), I(c),I(e), I(f), and I(h)) wherein R⁴ is R⁹—B—(CH₂)_(n)—; n is zero; B is—(C═O)—(R¹⁰—N)—, —(R¹⁰—N)—, —SO₂—(R¹⁰—N)—, —(R¹⁰—N)—(C═O)—(NR¹¹)— or—(R¹⁰—N)—(C═O)—O—; R⁹ is hydrogen or R¹³—(R¹²CH)_(m)—; more preferablywherein R⁹ is R¹³—(R¹²CH)_(m)—; m is 1 to 6; R¹⁰ is hydrogen or methyl;each R¹² is independently selected from the groups consisting ofhydrogen or methyl; and R¹³ is as described above, in combination withthe aforementioned embodiments of R².

Another more preferred embodiment of the present invention is that groupof compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) whereinR⁴ is R⁹—B—(CH₂)_(n)—; n is zero; B is —(R¹⁰—N)—; R⁹ is hydrogen orR¹³—(R¹²CH)_(m)—; m is 1 to 6; R¹⁰ is hydrogen or methyl; R¹² ishydrogen or methyl; and R¹³ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkyl.Other embodiments of the present invention include those compounds offormula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴ isR⁹—B—(CH₂)_(n)—; n is zero; B is —(R¹⁰—N)—; R⁹ is hydrogen or R¹³—(R2CH)_(m)—; m is 1 to −6; R¹⁰ is hydrogen or methyl; R¹² is hydrogen ormethyl; and R¹³ is selected from the group consisting of hydrogen,(C₁-C₅)alkyl, hydroxy, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkyl, incombination with the aforementioned embodiments of R¹ and R². Morepreferred embodiments of the invention is that group of compounds offormula I (and I(c), I(e) and I(f)) wherein R⁴ is R⁹—B—(CH₂)_(n)—, n iszero, B is —(R¹⁰—N)—, R⁹ is R¹³—(R¹²CH)_(m), m is 1 to 6, and R¹⁰, R¹²and R¹³ are each hydrogen.

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴ isR⁹—B—(CH₂)_(n)—; n is zero; B is a bond, and R⁹ is selected from thegroup consisting of optionally substituted phenyl, (C₁-C₁₀)heterocyclic,(C₁-C₁₀)heteroaryl and (C₃-C₁₀)cycloalkyl; wherein each of the aforesaidR⁹ phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic and(C₃-C₁₀)cycloalkyl substituents may optionally be substituted by one tofour moieties independently selected from the group consisting of halo,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl,hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy,(C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—,(C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—NH—, phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN,(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)— (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—. Other embodiments of thepresent invention include those compounds of formula I (and I(a), I(c),I(e), I(f), and I(h)) wherein R⁴ is R⁹—B—(CH₂)_(n)—; n is zero; B is abond, and R⁹ is as described above, in combination with theaforementioned embodiments of R².

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴ isR⁹—B—(CH₂)_(n)—; n is zero; B is —(C═O)—(R¹⁰—N)—, —(R¹⁰—N)—,—SO₂—(R¹⁰—N)—, —(R¹⁰—N)—(C═O)—(NR¹¹)— or —(R¹⁰—N)—(C═O)—O—; and R⁹ isselected from the group consisting of optionally substituted phenyl,(C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl and (C₃-C₁₀)cycloalkyl; whereineach of the aforesaid R⁹ phenyl, (C₁-C₁₀)heteroaryl,(C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkyl substituents may optionallybe substituted by one to four moieties independently selected from thegroup consisting of halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,perhalo(C₁-C₆)alkyl, phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic,(C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,phenoxy, (C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—,(C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═)—, H₂N(C═O)—(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—. Other embodiments of thepresent invention include those compounds of formula I (and I(a), I(c),I(e), I(f), and I(h)) wherein R⁴ is R⁹—B—(CH₂)_(n)—; n is zero; B is—(C═O)—(R¹⁰—N)—, —(R¹⁰—N)—, —SO₂—(R¹⁰—N)—, —(R¹⁰—N)—(C═O)—(NR¹)— or—(R¹⁰—N)—(C═O)—O—; and R⁹ is as described above, in combination with theaforementioned embodiments of R².

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴ isR⁹—B—(CH₂)_(n)—; n is an integer from one to six, more preferably one tofive, more preferably one to three; B is a bond, and R⁹ is selected fromthe group consisting of optionally substituted phenyl,(C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl and (C₃-C₁₀)cycloalkyl; whereineach of the aforesaid R⁹ phenyl, (C₁-C₁₀)heteroaryl,(C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkyl substituents may optionallybe substituted by one to four moieties independently selected from thegroup consisting of halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,perhalo(C₁-C₆)alkyl, phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic,(C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,phenoxy, (C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—,(C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—. Other embodiments of thepresent invention include those compounds of formula I (and I(a), I(c),I(e), I(f), and I(h)) wherein R⁴ is R⁹—B—(CH₂)_(n)—; n is an integerfrom one to six, more preferably one to five, more preferably one tothree; B is a bond, and R⁹ is as described above, in combination withthe aforementioned embodiments of R².

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴ isR⁹—B—(CH₂)_(n)—; n is an integer from one to six, more preferably one tofive, more preferably one to three; B is —(C═O)—(R¹⁰—N)—, —(R¹⁰—N)—,—SO₂—(R¹⁰—N)—, —(R¹⁰—N)—(C═O)—(NR¹¹)— or —(R¹⁰—N)—(C═O)—O—; and R⁹ isselected from the group consisting of optionally substituted phenyl,(C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl and (C₃-C₁₀)cycloalkyl; whereineach of the aforesaid R⁹ phenyl, (C₁-C₁₀)heteroaryl,(C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkyl substituents may optionallybe substituted by one to four moieties independently selected from thegroup consisting of halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,perhalo(C₁-C₆)alkyl, phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic,(C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,phenoxy, (C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—,(C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—. Other embodiments of thepresent invention include those compounds of formula I (and I(a), I(c),I(e), I(f), and I(h)) wherein R⁴ is R⁹—B—(CH₂)_(n)—; n is an integerfrom one to six, more preferably one to five, more preferably one tothree; B is —(C═O)—(R¹⁰—N)—, —(R¹⁰—N)—, —SO₂—(R¹⁰—N)—,—(R¹⁰—N)—(C═O)—(NR¹¹)— or —(R¹⁰—N)—(C═O)—O—; and R⁹ is as describedabove, in combination with the aforementioned embodiments of R².

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴ isR⁹—B—(CH₂)_(n)—; n is an integer from one to six, more preferably one tofive, more preferably one to three; B is a bond, and R⁹ isR¹³—(R¹²CH)_(m)—; m is 1 to 6; R¹⁰ is hydrogen or methyl; each R¹² isindependently selected from the groups consisting of hydrogen or methyl;and R¹³ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic,(C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,phenoxy, (C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—,(C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₆)alkyl-SO₂—NH—, phenyl-SO₂—NH—,(C₁-C₆)alkyl-SO₂—[((C₁-C₆)alkyl)—N]—, phenyl-SO₂—[((C₁-C₆)alkyl)—N]—,—CN, (C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₁₀)heteroaryl-NH—(C═O)—, (C₁-C₁₀)heterocyclic-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,H₂N(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,phenyl-NH—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—. Other embodiments of thepresent invention include those compounds of formula I (and I(a), I(c),(e), I(f), and I(h)) wherein R⁴ is R⁹—B—(CH₂)_(n)—; n is an integer fromone to six, more preferably one to five, more preferably one to three; Bis a bond, and R⁹ is R¹³—(R²CH)_(m)—; m is 1 to 6; R¹⁰ is hydrogen ormethyl; each R¹² is independently selected from the groups consisting ofhydrogen or methyl; and R¹³ as described above, in combination with theaforementioned embodiments of R².

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R⁴ isR⁹—B—(CH₂)_(n)—; n is an integer from one to six, more preferably one tofive, more preferably one to three; B is —(C═O)—(R¹⁰—N)—, —(R¹⁰—N)—,—SO₂—(R¹⁰—N)—, —(R¹⁰—N)—(C═O)—(NR¹¹)— or —(R¹⁰—N)—(C═O)—O—; and R⁹ isR³—(R²CH)_(m)—; m is 1 to 6; R¹⁰ is hydrogen or methyl; each R¹² isindependently selected from the groups consisting of hydrogen or methyl;and R¹³ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic,(C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,phenoxy, (C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—,(C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₆)alkyl-SO₂—NH—, phenyl-SO₂—NH—,(C₁-C₆)alkyl-SO₂—[((C₁-C₆)alkyl)—N]—, phenyl-SO₂—[((C₁-C₆)alkyl)—N]—,—CN, (C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₁₀)heteroaryl-NH—(C═O)—, (C₁-C₁₀)heterocyclic-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,H₂N(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,phenyl-NH—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—. Other embodiments of thepresent invention include those compounds of formula I (and I(a), I(c),I(e), I(f), and I(h)) wherein R⁴ is R⁹—B—(CH₂)_(n)—; n is an integerfrom one to six, more preferably one to five, more preferably one tothree; B is —(C═O)—(R¹⁰—N)—, —(R¹⁰—N)—, —SO₂—(R¹⁰—N)—,—(R¹⁰—N)—(C═O)—(NR¹¹)— or —(R¹⁰—N)—(C═O)—O—; and R⁹ is R¹³—(R¹²CH)_(m)—;m is 1 to −6; R¹⁰ is hydrogen or methyl; each R¹² is independentlyselected from the groups consisting of hydrogen or methyl; and R¹³ is asdescribed above, in combination with the aforementioned embodiments ofR².

Another embodiment of the present invention is that group of compoundsof formula I (and I(c) and I(f)) wherein R⁷ is selected from the groupconsisting of hydrogen, phenyl, (C₁-C₁₀)heteroaryl,(C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, R¹⁶—(C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)— and (C₃-C₁₀)cycloalkyl-NH—(C═O)—; whereineach of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R⁷alternatives may optionally be independently substituted by one to fourmoieties independently selected from the group consisting of halo,R¹⁶—(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, phenyl, benzyl, (C₁-C₁₀)heterocyclic,(C₁-C₁₀)heteroaryl, (C₁-C₆)alkyl-SO₂—, formyl, —CN, (C₁-C₆)alkyl-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₁₀)heteroaryl-O—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—, (C₁-C₆)alkyl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—, phenyl-(C═O)—NH—,(C₁-C₁₀)heterocyclic-(C═O)—NH—, (C₁-C₁₀)heteroaryl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₆)alkyl-SO₂NH—,(C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH—and (C₁-C₁₀)heteroaryl-SO₂NH—; wherein each of said phenyl andheteroaryl moieties may optionally be substituted by one or two radicalsindependently selected from the group consisting of halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino and [(C₁-C₆)alkyl]₂-amino. Otherembodiments of the present invention include those compounds of formulaI (and I(c) and I(f)) wherein R⁷ is as defined above, in combinationwith each of the aforementioned I(c) and I(f) R⁴ embodiments and witheach of the aforementioned R² embodiments.

Another embodiment of the present invention is that group of compoundsof formula I (and I(c) and I(f)) wherein R⁷ is selected from the groupconsisting of R¹⁶—(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)— and (C₃-C₁₀)cycloalkyl-NH—(C═O)—; whereineach of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R⁷alternatives may optionally be independently substituted by one to fourmoieties independently selected from the group consisting of halo,R¹⁶—(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, phenyl, benzyl, (C₁-C₁₀)heterocyclic,(C₁-C₁₀)heteroaryl, (C₁-C₆)alkyl-SO₂—, formyl, —CN, (C₁-C₆)alkyl-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₁₀)heteroaryl-O—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—, (C₁-C₆)alkyl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—, phenyl-(C═O)—NH—,(C₁-C₁₀)heterocyclic-(C═O)—NH—, (C₁-C₁₀)heteroaryl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₈)alkyl-SO₂NH—,(C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH—and (C₁-C₁₀)heteroaryl-SO₂NH—; wherein each of said phenyl andheteroaryl moiety alternatives may optionally be substituted by one ortwo radicals independently selected from the group consisting of halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino and[(C₁-C₆)alkyl]₂-amino. Other embodiments of the present inventioninclude those compounds of formula I (and I(c) and I(f)) wherein R⁷ isas defined above, in combination with each of the aforementioned I(c)and I(f) R⁴ embodiments and with each of the aforementioned R²embodiments.

Another preferred embodiment of the present invention is that group ofcompounds of formula I (and I(c) and I(f)) wherein R⁷ is selected fromthe group consisting of hydrogen, and optionally substituted phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkyl. Otherembodiments of the present invention include those compounds of formulaI (and I(c) and I(f)) wherein R⁷ is as defined above, in combinationwith each of the aforementioned l(c) and I(f) R⁴ embodiments and witheach of the aforementioned R² embodiments. A more preferred embodimentof the present invention is that group of compounds of formula I(c)wherein R⁷ is hydrogen.

Another embodiment of the present invention is that group of compoundsof formula I (and I(c) and I(f)) wherein R⁷ is R¹⁴—(CR¹⁵H)_(p)—; p isone to six, preferably one to four; and R¹⁴ is selected from the groupconsisting of hydrogen, halo, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,perhalo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, phenyl, (C₁-C₁₀)heterocyclic,(C₁-C₁₀)heteroaryl, formyl, —CN, (C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, R¹⁶—(C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₁₀)heteroaryl-O—(C═O)—, H₂N—(C═O)—, R⁶—(C₁-C₆)alkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heteroaryl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heterocyclic-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₃-C₁₀)cycloalkyl-[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy,R¹⁶—(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—,R¹—(C₁-C₆)alkyl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, amino,R¹⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,R⁶—(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,phenyl-(C═O)—NH—, (C₁-C₁₀)heterocyclic-(C═O)—NH—,(C₁-C₁₀)heteroaryl-(C═O)—NH—,R¹⁶—(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—[(C₁-C₆)alkyl-N]—, R¹⁶—(C₁-C₆)alkyl-SO₂NH—,(C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH—and (C₁-C₁₀)heteroaryl-SO₂NH—; wherein each of the aforesaid phenyl,heterocyclic, heteroaryl or cycloalkyl R¹⁴ alternatives may optionallybe independently substituted by one to four moieties independentlyselected from the group consisting of halo, R¹⁶—(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,phenyl, benzyl, (C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl,(C₁-C₆)alkyl-SO₂—, formyl, —CN, R¹⁶—(C₁-C₆)alkyl-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₁₀)heteroaryl-O—(C═O)—, H₂N—(C═O)—, R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy,R¹⁶—(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—,R¹⁶—(C₁-C₆)alkyl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,R¹⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,phenyl-(C═O)—NH—, (C₁-C₁₀)heterocyclic-(C═O)—NH—,(C₁-C₁₀)heteroaryl-(C═O)—NH—,R¹⁶-(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, R¹⁶—(C₁-C₆)alkyl-SO₂NH—,(C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH—and (C₁-C₁₀)heteroaryl-SO₂NH—; wherein each of said phenyl andheteroaryl moiety alternatives may optionally be substituted by one ortwo radicals independently selected from the group consisting of halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino or[(C₁-C₆)alkyl]₂-amino;

each R¹⁵ is independently selected from the group consisting ofhydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, perhalo(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₈)alkoxy,amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl and(C₁-C₈)alkyl-(C═O)—NH—; and

each R¹⁶ is independently selected from the group consisting ofhydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,perhalo(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—O—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl and(C₁-C₆)alkyl-(C═O)—NH—. Other embodiments of the present inventioninclude those compounds of formula I (and I(c) and I(f)) wherein R⁷ isas defined above, in combination with each of the aforementioned I(c)and I(f) R⁴ embodiments and with each of the aforementioned R²embodiments.

Another preferred embodiment of the present invention is that group ofcompounds of formula I (and I(c) and I(f)) wherein R⁷ isR¹⁴—(CR¹⁵H)_(p)—; p is one to four; R¹⁴ is selected from the groupconsisting of hydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₃-C₁₀)cycloalkyl, phenyl, (C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl,HO—(C═O)—, R¹⁶—(C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,phenyl-[N—((C₁-C₆)alkyl)]—(C═O)—, hydroxy, R¹⁶—(C₁-C₆)alkoxy, phenoxy,amino, R¹⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino andR¹⁶—(C₁-C₆)alkyl-(C═O)—NH—; wherein each of the aforesaid phenyl,heterocyclic, heteroaryl or cycloalkyl R¹⁴ alternatives may optionallybe independently substituted by one to four moieties independentlyselected from the group consisting of halo, R¹⁶—(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, (C₁-C₆)alkyl-SO₂—,formyl, —CN, R¹⁶—(C₁-C₆)alkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,H₂N—(C═O)—, R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,hydroxy, R¹⁶—(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,R¹⁶—(C₁-C₆)alkyl-(C═O)—O—, amino, R¹⁶—(C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, formamidyl, R¹⁶-(C₁-C₆)alkyl-(C═O)—NH—,R¹⁶—(C₁-C₆)alkyl-(C═O)—[((C-C₆)alkyl)—N]— and R¹⁶—(C₁-C₆)alkyl-SO₂NH—;

each R¹⁵ is independently selected from the group consisting ofhydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, perhalo(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl and(C₁-C₆)alkyl-(C═O)—NH—; wherein no more than two of said R¹⁵ groups maybe other than hydrogen; and

each R¹⁶ is independently selected from the group consisting ofhydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,perhalo(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—O—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl and(C₁-C₆)alkyl-(C═O)—NH—. Other embodiments of the present inventioninclude those compounds of formula I (and I(c) and I(f)) wherein R⁷ isas defined above, in combination with each of the aforementioned I(c)and I(f) R⁴ embodiments and with each of the aforementioned R²embodiments.

A more preferred embodiment of the present invention are those group ofcompounds of formula I(c) wherein R⁷ is R¹⁴—(CR¹⁵H)_(p)—; p is one tofour; R¹⁴ is selected from the group consisting of hydrogen,(C₂-C₄)alkenyl, HO—(C═O)—, (C₁-C₃)alkyl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₃)alkyl-NH—(C═O)—, [(C₁-C₂)alkyl]₂—N—(C═O)—, hydroxy,(C₁-C₃)alkoxy, amino, (C₁-C₄)alkylamino, [(C₁-C₄)alkyl]₂-amino and(C₁-C₃)alkyl-(C═O)—NH—; and each R¹⁵ is independently selected from thegroup consisting of hydrogen, (C₁-C₂)alkyl, hydroxy, and amino. Morepreferred compounds of formula I(c) are those compounds wherein thecombined molecular weight of the R⁴ and R⁷ substituents is less than 200AMU. More preferably, the combined molecular weight of the R⁴ and R⁷substituents is less than 100 AMU.

Another embodiment of the present invention is that group of compoundsof formula I (and I(b)) wherein R⁵ is hydrogen. Other embodiments of thepresent invention include those compounds of formula I (and I(b))wherein R⁵ is hydrogen, in combination with each of the aforementionedR² embodiments.

Another preferred embodiment of the present invention is that group ofcompounds of formula I (and I(b)) wherein R⁵ is (C₁-C₁₀)heterocyclic or(C₁-C₁₀)heteroaryl; wherein each of the aforesaid heterocyclic andheteroaryl substituents may optionally be independently substituted byone to four moieties independently selected from the group consisting ofhalo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)— and [(C₁-C₆)alkyl]₂—N—(C═O)—. Otherembodiments of the present invention include those compounds of formulaI (and I(b)) wherein R⁵ is said optionally substituted(C₁-C₁₀)heterocyclic or (C₁-C₁₀)heteroaryl, in combination with each ofthe aforementioned R² embodiments. More preferred heterocyclic groupsare pyrrolidinyl, piperidinyl and azetidinyl.

Another preferred embodiment of the present invention is that group ofcompounds of formula I (and I(b)) wherein R⁵ is R¹⁴—(CHR¹⁵)_(p)—, p is 1to 6; and R¹⁴ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, perhalo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,phenyl, (C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl, phenyl-(S═O)—,(C₁-C₆)alkyl-SO₂, phenyl-SO₂—, H₂N—SO₂—, (C₁-C₆)alkyl-NH—SO₂—,phenyl-NH—SO₂—, [(C₁-C₆)alkyl-]₂N—SO₂—, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₁₀)heteroaryl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heteroaryl-[N—(C₁-C₆)alkyl]-(C═O)—,(C₁-C₁₀)heterocyclic-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₃-C₁₀)cycloalkyl[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy, R¹⁶(—C₆)alkoxy,perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—,R⁶—(C₁-C₆)alkyl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,R¹⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,phenyl-(C═O)—NH—, R⁶—(C₁-C₆)alkyl-SO₂NH—, (C₃-C₁₀)cycloalkyl-SO₂NH—,phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH— and(C₁-C₁₀)heteroaryl-SO₂NH—; wherein each of the aforesaid phenyl,heterocyclic, heteroaryl or cycloalkyl R¹⁴ alternatives may optionallybe independently substituted by one to four moieties independentlyselected from the group consisting of halo, R¹⁶—(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,phenyl, benzyl, (C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl,(C₁-C₆)alkyl-SO₂—, formyl, —CN, R¹⁶—(C₁-C,)alkyl-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₁₀)heteroaryl-O—(C═O)—, H₂N—(C═O)—, R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy,R¹⁶—(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—,R¹⁶—(C₁-C₆)alkyl-(C═O)—O—, (C₃-clo)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,R¹⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,phenyl-(C═O)—NH—, (C₁-C₁₀)heterocyclic-(C═O)—NH—,(C₁-C₁₀)heteroaryl-(C═O)—NH—,R¹⁶—(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—[(C₁-C₆)alkyl-N]—, R¹⁶—(C₁-C₆)alkyl-SO₂NH—,(C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH—and (C₁-C₁₀)heteroaryl-SO₂NH—; and wherein each of said phenyl andheteroaryl moiety alternatives may optionally be substituted by one ortwo radicals independently selected from halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino and [(C₁-C₆)alkyl]₂-amino. Otherembodiments of the present invention include those compounds of formulaI (and I(b)) wherein R⁵ is said R¹⁴—(CHR¹⁵)_(p)—, p is I to −6; and R¹⁴is as defined above, in combination with each of the aforementioned R²embodiments.

Another preferred embodiment of the present invention is that group ofcompounds of formula I (and I(b)) wherein R⁵ is R¹⁴—(CHR¹⁵)_(p)—, p is 1to 6; and R¹⁴ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₃-C₁₀)cycloalkyl, phenyl,(C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,phenyl-NH—(C═O)—, (C₁-C₁₀)heterocyclic-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy,R¹⁶—(C₁-C₆)alkoxy, phenoxy, amino, R¹⁵—(C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—; wherein each of theaforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R¹⁴substituents may optionally be independently substituted by one to fourmoieties independently selected from the group consisting of halo,R¹⁶—(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,(C₁-C₆)alkyl-SO₂₇, formyl, —CN, R¹⁶—(C₁-C₆)alkyl-(C═O)—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—, R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy, R¹⁶—(C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, R¹⁶—(C₁-C₆)alkyl-(C═O)—O—, amino,R¹⁶—(C₁-C₆)alkylamino, [(C—C₆)alkyl]₂-amino, formamidyl,R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—, R¹⁶—(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)-N]—and R¹⁶—(C₁-C₆)alkyl-SO₂NH—;

each R¹⁵ is independently selected from the group consisting ofhydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, perhalo(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl and(C₁-C₆)alkyl-(C═O)—NH—; wherein no more than two of said R¹⁵ groups maybe other than hydrogen; and

each R¹⁶ is independently selected from the group consisting ofhydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,perhalo(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—O—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl and(C₁-C₆)alkyl-(C═O)—NH—.

Other embodiments of the present invention include that group ofcompounds of formula I (and I(b)) wherein R⁵ is said R¹⁴—(CHR¹⁵)_(p)—, pis 1 to 6; and R¹⁴, R¹⁵ and R¹⁶ are as defined above, in combinationwith each of the aforementioned R² embodiments.

A more preferred embodiment of the present invention are those group ofcompounds of formula I (and I(b)) wherein R⁵ is R¹⁴—(CHR¹⁵)_(p)—, p is 1to 6; and R¹⁴ is selected from the group consisting of hydrogen,(C₂-C₄)alkenyl, (C₁-C₁₀)heterocyclic, HO—(C═O)—, (C₁-C₃)alkyl-O—(C═O)—,H₂N—(C═O)—, (C₁-C₃)alkyl-NH—(C═O)—, hydroxy, (C₁-C₃)alkoxy, amino,(C₁-C₃)alkylamino, and [(C₁-C₂)alkyl]₂-amino; and each R¹⁵ isindependently selected from the group consisting of hydrogen,(C₁-C₆)alkyl, hydroxy, (C₁-C₃)alkoxy, perhalo(C₁)alkoxy, amino,(C₁-C₂)alkylamino, [(C₁-C₂)alkyl]₂-amino, formamidyl and(C₁-C₆)alkyl-(C═O)—NH—; wherein no more than two of said R¹⁵ groups maybe other than hydrogen.

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(b), I(d), I(g)) wherein R⁶ is hydrogen. Otherembodiments of the present invention include those compounds of formulaI (and I(a), I(b), I(d), I(g)) wherein R⁶ is hydrogen, in combinationwith each of the aforementioned I(a) R⁴ embodiments, I(b) R⁵ embodimentsor with each of the aforementioned R² embodiments.

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(b), I(d), I(g)) wherein R⁶ is R⁹—B—(CH₂)_(n)—and n is zero. Other embodiments of the present invention include thosecompounds of formula I (and I(a), I(b), I(d), I(g)) wherein R⁶ isR⁹—B—(CH₂)_(n)— and n is zero, in combination with each of theaforementioned I(a) R⁴ embodiments, I(b) R⁵ embodiments or with each ofthe aforementioned R² embodiments.

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(b), I(d), I(g)) wherein R⁶ is R⁹—B—(CH₂)_(n)—and n is an integer from one to six, more preferably from one to five.Other embodiments of the present invention include those compounds offormula I (and I(a), I(b), I(d), I(g)) wherein R⁶ is R⁹—B—(CH₂)_(n)— andn is an integer from one to six, more preferably from one to five, incombination with each of the aforementioned I(a) R⁴ embodiments, I(b) R⁵embodiments or with each of the aforementioned R² embodiments.

Another preferred embodiment of the present invention is that group ofcompounds of formula I (and I(a), I(b), I(d), I(g)) wherein R⁶ isR⁹—B—(CH₂)_(n)—; n is zero; B is a bond and R⁹ is selected from thegroup consisting of hydrogen, —CF₃, —C≡N, (C₁-C₁₀)heteroaryl,(C₁-C₁₀)heterocyclic or (C₃-C₁₀)cycloalkyl; wherein each of theaforesaid (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic and(C₃-C₁₀)cycloalkyl may optionally be substituted by one to threemoieties independently selected from the group consisting of halo,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkynyl, perhalo(C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN, (C₁-C₆)alkyl-(C═O)—,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]2-N—(C═O)— and (C₁-C₆)alkyl-(C═O)—O—. Other embodiments ofthe present invention include those compounds of formula I (and I(a),I(b), I(d), I(g)) wherein R⁶ is R⁹—B—(CH₂)_(n)— and n is zero; B is abond and R⁹ is as defined above, in combination with each of theaforementioned I(a) R⁴ embodiments, I(b) R⁵ embodiments or with each ofthe aforementioned R² embodiments.

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(b), I(d), I(g)) wherein R⁶ is R⁹—B—(CH₂)_(n)—;n is zero; B is —(C═O)—NR¹⁰—, —(R¹⁰—N)—, —(R¹⁰—N)—SO₂—,—(R¹⁰—N)—(C═O)—, >C═O, —O—(C═O)—, —SO₂—(NR¹¹)—, —(R¹⁰—N)—(C═O)—(NR¹¹)—;and

R⁹ is selected from the group consisting of hydrogen, (C₃-C₁₀)cycloalkylor phenyl; wherein the aforesaid phenyl and (C₃-C₁₀)cycloalkyl mayoptionally be substituted by one to three moieties independentlyselected from the group consisting of halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₈)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[N(C₁-C₆)alkyl]—, —CN, (C₁-C₆)alkyl-(C═O)—,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)— (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)— and (C₁-C₆)alkyl-(C═O)—O—. Other embodiments ofthe present invention include those compounds of formula I (and I(a),I(b), I(d), I(g)) wherein R⁶ is R⁹—B—(CH₂)_(n)— and n is zero; B is—(C═O)—NR¹⁰—, —(R¹⁰—N)—, —(R¹⁰—N)—SO₂—, —(R¹⁰—N)—(C═O)—, >C═O,—O—(C═O)—, —SO₂—(NR¹⁰)—, —(R¹⁰—N)—(C═O)—(NR¹¹)—; and R⁹ is as definedabove, in combination with each of the aforementioned I(a) R⁴embodiments, I(b) R⁵ embodiments or with each of the aforementioned R²embodiments.

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(b), I(d), I(g)) wherein R⁶ is R⁹—B—(CH₂)_(n)—;n is zero; B is a bond; R⁹ is R¹³—(R¹²CH)_(m)—; m is 1 to 6; R¹⁰ ishydrogen or methyl; R¹² is hydrogen or methyl; and R¹³ is selected fromthe group consisting of hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-SO₂—NH—,phenyl-SO₂—NH—, (C₁-C₆)alkyl-SO₂—[N—(C₁-C₆)alkyl]-,phenyl-SO₂—[N—(C₁-C₆)alkyl]-, hydroxy, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, phenoxy, (C₁-C₁₀)heteroaryl-O—,(C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[N(C₁-C₆)alkyl]-, phenyl-(C═O)—NH—,phenyl-(C═O)—[N—(C₁-C₆)alkyl]-, —CN, (C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[N—((C₁-C₆)alkyl)]—(C═O)—, (C₁-C₆)alkyl-(C═O)—O— andphenyl-(C═O)—O—. Other embodiments of the present invention includethose compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R⁶ isR⁹—B—(CH₂)_(n)— and n is zero; B is a bond; R⁹ is R¹³—(R¹²CH)_(m)—; m is1 to 6; R¹⁰ is hydrogen or methyl; R¹² is hydrogen or methyl; and R¹³ isas defined above, in combination with each of the aforementioned I(a) R⁴embodiments, I(b) R⁵ embodiments or with each of the aforementioned R²embodiments.

Another preferred embodiment of the present invention is that group ofcompounds of formula I (and I(a), I(b), I(d), I(g)) wherein R⁶ isR⁹—B—(CH₂)_(n)—; n is zero; B is —(C═O)—NR¹⁰—, —(R¹⁰—N)—, >C═O,—O—(C═O)—, —(R¹⁰—N)—(C═O)— or —(R¹⁰—N)—(C═O)—(NR¹¹)—; R⁹ isR¹³—(R¹²CH)_(m)—; m is 1 to 6; R¹⁰ is hydrogen or methyl; R¹² ishydrogen or methyl; and R¹³ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, phenyl, (C₁-C₁₀)heteroaryl,(C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-SO₂—NH—, phenyl-SO₂—NH—,(C₁-C₆)alkyl-SO₂—[N—(C₁-C₆)alkyl]-, phenyl-SO₂—[N—(C₁-C₆)alkyl]-,hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy,(C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—,(C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—[N(C₁-C₆)alkyl]-,phenyl-(C═O)—NH—, phenyl-(C═O)—[N—(C₁-C₆)alkyl]-, —CN,(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₁₀)heteroaryl-NH—(C═O)—, (C₁-C₁₀)heterocyclic-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,H₂N(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,phenyl-NH—(C═O)—, phenyl-[N—((C₁-C₆)alkyl)]—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—. Other embodiments of thepresent invention include those compounds of formula I (and I(a), I(b),I(d), I(g)) wherein R⁶ is R⁹—B—(CH₂)_(n)— and n is zero; B is—(C═O)—NR¹⁰—, —(R¹⁰—N)—, —(R¹⁰—N)—SO₂—, —(R¹⁰—N)—(C═O)—, >C═O,—O—(C═O)—, —SO₂—(NR¹⁰)—, —(R¹⁰—N)—(C═O)—(NR¹¹)—; and R⁹ isR¹³—(R¹²CH)_(m)—; m is 1 to 6; R¹⁰ is hydrogen or methyl; R¹² ishydrogen or methyl; and R¹³ is as defined above, in combination witheach of the aforementioned I(a) R⁴ embodiments, I(b) R⁵ embodiments orwith each of the aforementioned R² embodiments.

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(b), I(d), I(g)) wherein R⁶ is R⁹—B—(CH₂)_(n)—;n is an integer from one to six, more preferably one to five, morepreferably one to three; B is a bond, and R⁹ is selected from the groupconsisting of optionally substituted phenyl, (C₁-C₁₀)heterocyclic,(C₁-C₁₀)heteroaryl and (C₃-C₁₀)cycloalkyl; wherein each of the aforesaidR⁹ phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic and(C₃-C₁₀)cycloalkyl substituents may optionally be substituted by one tofour moieties independently selected from the group consisting of halo,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl,hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy,(C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—,(C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino,(C₁-C₆)alkylamino, [(C-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—NH—, phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN,(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)— (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—. Other embodiments of thepresent invention include those compounds of formula I (and I(a), I(b),I(d), I(g))wherein R⁶ is R⁹—B—(CH₂)_(n)—; n is an integer from one tosix, more preferably one to five, more preferably one to three; B is abond, and R⁹ is as described above, in combination with each of theaforementioned I(a) R⁴ embodiments, I(b) R⁵ embodiments or with each ofthe aforementioned R² embodiments.

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(b), I(d), I(g)) wherein R⁶ is R⁹—B—(CH₂)_(n)—;n is an integer from one to six, more preferably one to five, morepreferably one to three; B is —(C═O)—(R¹⁰—N)—, —(R¹⁰—N)—, —SO₂—(R¹⁰—N)—,—(R¹⁰—N)—(C═O)—(NR¹¹)— or —(R¹⁰—N)—(C═O)—O—; and R⁹ is selected from thegroup consisting of optionally substituted phenyl, (C₁-C₁₀)heterocyclic,(C₁-C₁₀)heteroaryl and (C₃-C₁₀)cycloalkyl; wherein each of the aforesaidR⁹ phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic and(C₃-C₁₀)cycloalkyl substituents may optionally be substituted by one tofour moieties independently selected from the group consisting of halo,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl,hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy,(C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—,(C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—NH—, phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN,(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)— (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—. Other embodiments of thepresent invention include those compounds of formula I (and I(a), I(b),I(d), I(g)) wherein R⁶ is R⁹—B—(CH₂)_(n)—; n is an integer from one tosix, more preferably one to five, more preferably one to three; B is—(C═O)—(R¹⁰—N)—, —(R¹⁰—N)—, —SO₂—(R¹⁰—N)—, —(R¹⁰—N)—(C═O)—(NR¹¹)— or—(R¹⁰—N)—(C═O)—O—; and R⁹ is as described above, in combination witheach of the aforementioned I(a) R⁴ embodiments, I(b) R⁵ embodiments orwith each of the aforementioned R² embodiments.

Another embodiment of the present invention is that group of compoundsof formula I (and I(a), I(b), I(d), I(g)) wherein R⁶ is R⁹—B—(CH₂)_(n)—;n is an integer from one to six, more preferably one to five, morepreferably one to three; B is a bond, and R⁹ is R¹³—(R¹²CH)_(m)—; m is 1to 6; R¹⁰ is hydrogen or methyl; each R¹² is independently selected fromthe groups consisting of hydrogen or methyl; and R¹³ is selected fromthe group consisting of hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy, (C₁-C₁₀)heteroaryl-O—,(C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₆)alkyl-SO₂—NH—, phenyl-SO₂—NH—,(C₁-C₆)alkyl-SO₂—[((C₁-C₆)alkyl)—N]—, phenyl-SO₂—[((C₁-C₆)alkyl)—N]—,—CN, (C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₁₀)heteroaryl-NH—(C═O)—, (C₁-C₁₀)heterocyclic-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,H₂N(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,phenyl-NH—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—. Other embodiments of thepresent invention include those compounds of formula I (and I(a), I(c),I(e), I(f), and I(h)) wherein R⁶ is R⁹—B—(CH₂)_(n)—; n is an integerfrom one to six, more preferably one to five, more preferably one tothree; B is —(C═O)—(R¹⁰—N)—, —(R¹⁰—N)—, —SO₂—(R¹⁰—N)—,—(R¹⁰—N)—(C═O)—(NR¹¹)— or —(R¹⁰—N)—(C═O)—O—; R⁹ is R¹³—(R¹²CH)_(m)—; mis 1 to 6; R¹⁰ is hydrogen or methyl; each R¹² is independently selectedfrom the groups consisting of hydrogen or methyl; and R¹³ is asdescribed above, in combination with each of the aforementioned I(a) R⁴embodiments, I(b) R⁵ embodiments or with each of the aforementioned R²embodiments.

Another preferred embodiment of the present invention is that group ofcompounds of formula I (and I(a), I(b), I(d), I(g)) wherein R⁶ isR⁹—B—(CH₂)_(n)—; n is an integer from one to six; B is —(C═O)—NR¹⁰—,—(R¹⁰—N)—, >C═O, —O—(C═O)—, —(R¹⁰—N)—(C═O)— or —(R¹⁰—N)—(C═O)—(NR¹¹)—;R⁹ is R¹³—(R¹²CH)_(m)—; m is 1 to 6; R¹⁰ is hydrogen or methyl; R¹² ishydrogen or methyl; and R¹³ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, phenyl, (C₁-C₁₀)heteroaryl,(C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-SO₂—NH—, phenyl-SO₂—NH—,(C₁-C₆)alkyl-SO₂—[N—(C₁-C₆)alkyl]-, phenyl-SO₂—[N—(C₁-C₆)alkyl]-,hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy,(C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—,(C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—[N(C₁-C₆)alkyl]-,phenyl-(C═O)—NH—, phenyl-(C═O)—[N—(C₁-C₆)alkyl]-, —CN,(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₁₀)heteroaryl-NH—(C═O)—, (C₁-C₁₀)heterocyclic-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,H₂N(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,phenyl-NH—(C═O)—, phenyl-[N—((C₁-C₆)alkyl)]—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—. Other embodiments of thepresent invention include those compounds of formula I (and I(a), I(b),I(d), I(g)) wherein R⁶ is R⁹—B—(CH₂)_(n)— and n is 1 to 6; B is—(C═O)—NR¹⁰—, —(R¹⁰—N)—, —(R¹⁰—N)—SO₂—, —(R¹⁰—N)—(C═O)—, >C═O,—O—(C═O)—, —SO₂—(NR¹⁰)—, —(R¹⁰—N)—(C═O)—(NR¹¹)—; and R⁹ isR³—(R²CH)_(m)—; m is 1 to 6; R¹⁰ is hydrogen or methyl; R¹² is hydrogenor methyl; and R¹³ is as defined above, in combination with each of theaforementioned I(a) R⁴ embodiments, I(b) R⁵ embodiments or with each ofthe aforementioned R² embodiments.

An embodiment of the present invention is that group of compounds offormula I wherein s is an integer from zero to four and each R³ isindependently selected from the group consisting of halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy, (C₁-C₁₀)heteroaryl-O—,(C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)— and(C₁-C₆)alkyl-(C═O)—O—. Other embodiments of the present inventioninclude those compounds of formula I (and I(a), I(b), I(c), I(d), I(e),I(f) and I(g)) wherein R³ is as defined above in combination with eachof the aforementioned R⁶ embodiments, R⁷ embodiments, R⁴ embodiments, R⁵embodiments or with each of the aforementioned R² embodiments.

Another embodiment of the present invention is that group of compoundsof formula I wherein s is an integer from zero to four and each R³ isindependently selected from the group consisting of halo, —CN,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and perhalo(C₁-C₆)alkyl.Other embodiments of the present invention include those compounds offormula I (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R³is as defined above in combination with each of the aforementioned R⁶embodiments, R⁷ embodiments, R⁴ embodiments, R⁵ embodiments or with eachof the aforementioned R² embodiments.

Another embodiment of the present invention is that group of compoundsof formula I wherein s is an integer from zero to four and zero, one ortwo of R³ are independently selected from the group consisting of halo,(C₁-C₆)alkyl, perhalo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino,—CN, and H₂N(C═O)—. Other embodiments of the present invention includethose compounds of formula I (and I(a), I(b), I(c), I(d), I(e), I(f) andI(g)) wherein R³ is as defined above in combination with each of theaforementioned R⁶ embodiments, R⁷ embodiments, R⁴ embodiments, R⁵embodiments or with each of the aforementioned R² embodiments.

Another embodiment of the present invention is that group of compoundsof formula I wherein s is an integer from zero to four and one of R³ isselected from the group consisting of optionally substituted phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkyl. Otherembodiments of the present invention include those compounds of formulaI (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R³ is asdefined above in combination with each of the aforementioned R⁶embodiments, R⁷ embodiments, R⁴ embodiments, R⁵ embodiments or with eachof the aforementioned R² embodiments.

Another embodiment of the present invention is that group of compoundsof formula I wherein s is an integer from zero to four and one of R³ isselected from the group consisting of hydroxy, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, phenoxy, (C₁-C₁₀)heteroaryl-O—,(C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂— and (C₁-C₆)alkyl-NH—SO₂—. Other embodiments of thepresent invention include those compounds of formula I (and I(a), I(b),I(c), I(d), I(e), I(f) and I(g)) wherein R³ is as defined above incombination with each of the aforementioned R⁶ embodiments, R⁷embodiments, R⁴ embodiments, R⁵ embodiments or with each of theaforementioned R² embodiments.

Another embodiment of the present invention is that group of compoundsof formula I wherein s is an integer from zero to four and one of R³ isselected from the group consisting of amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH— andphenyl-(C═O)—[N—(C₁-C₆)alkyl]-. Other embodiments of the presentinvention include those compounds of formula I (and I(a), I(b), I(c),I(d), I(e), I(f) and I(g)) wherein R³ is as defined above in combinationwith each of the aforementioned R³ embodiments, R⁷ embodiments, R⁴embodiments, R⁵ embodiments or with each of the aforementioned R²embodiments.

Another embodiment of the present invention is that group of compoundsof formula I wherein s is an integer from zero to four and one of R³ isselected from the group consisting of (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)— (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)— and (C₁-C₆)alkyl-(C═O)—O—. Otherembodiments of the present invention include those compounds of formulaI (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R³ is asdefined above in combination with each of the aforementioned R⁶embodiments, R⁷ embodiments, R⁴ embodiments, R⁵ embodiments or with eachof the aforementioned R² embodiments.

Another embodiment of the present invention is that group of compoundsof formula I wherein s is an integer from zero to three and each R³ isindependently selected from the group consisting of halo, (C₁-C₆)alkyl,perhalo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, —NO₂,amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, —CN, and H₂N(C═O)—.Other embodiments of the present invention include those compounds offormula I (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R³is as defined above in combination with each of the aforementioned R⁶embodiments, R⁷ embodiments, R⁴ embodiments, R⁵ embodiments or with eachof the aforementioned R² embodiments.

Preferred compounds of the present invention is that group of compoundsof formula I wherein s is an integer from zero to two and each R³ isindependently selected from the group consisting of halo, (C₁-C₆)alkyl,perhalo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy and —CN. Otherembodiments of the present invention include those compounds of formulaI (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R³ is asdefined above in combination with each of the aforementioned R⁶embodiments, R⁷ embodiments, R⁴ embodiments, R⁵ embodiments or with eachof the aforementioned R² embodiments.

More preferred compounds of the present invention is that group ofcompounds of formula I wherein s is an integer from zero to three andeach R³ is independently selected from the group consisting of fluoro,chloro and methyl. Other embodiments of the present invention includethose compounds of formula I (and I(a), I(b), I(c), I(d), I(e), I(f) andI(g)) wherein R³ is as defined above in combination with each of theaforementioned R⁶ embodiments, R⁷ embodiments, R⁴ embodiments, R⁵embodiments or with each of the aforementioned R² embodiments.

An embodiment of the (isoxazole-5-yl)-benzoimidazoles are thosecompounds wherein R⁴ is hydrogen. Another embodiment of the(isoxazole-5-yl)-benzoimidazoles are those compounds wherein R⁴ is otherthan hydrogen.

Examples of specific preferred compounds of the formula I are thefollowing:

6-[5-(4-fluoro-3-methyl-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;

6-[4-(4-fluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;

6-[5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;

6-[4-(4-fluoro-3-methyl-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;

6-[4-(4-Fluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;

1-Isopropyl-6-(5-phenyl-3H-imidazol-4-yl)-1H-benzotriazole;

1-Isopropyl-6-(4-phenyl-oxazol-5-yl)-1H-benzotriazole;

6-[5-(4-fluoro-3-methyl-phenyl)-3H-imidazol-4-y]-1-methyl-1H-benzotriazole;

6-[5-(4-fluoro-phenyl)-2-pyridin-3-yl-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;and

6-[5-(4-fluoro-phenyl)-2-pyrazin-2-yl-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole.

Examples of other compounds of the formula I are the following:

6-[5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-1-methyl-1H-benzotriazole;

1-methyl-6-(5-m-tolyl-3H-imidazol-4-yl)-1H-benzotriazole;

1-methyl-6-(5-phenyl-3H-imidazol-4-yl)-1H-benzotriazole;

1-Ethyl-6-(4-m-tolyl-oxazol-5-yl)-1H-benzotriazole;

1-Ethyl-6-(5-m-tolyl-3H-imidazol-4-yl)-1H-benzotriazole;

1-Ethyl-6-[4-(4-fluoro-phenyl)-oxazol-5-yl]-1H-benzotriazole;

1-Ethyl-6-[5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-1H-benzotriazole;

6-[3-benzyl-5-(4-fluoro-3-methyl-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;

6-[5-(4-fluoro-phenyl)-3S-pyrrolidin-3-yl-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazolemono citrate salt;

6-[5-(4-fluoro-phenyl)-3R-pyrrolidin-3-yl-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;

1-methyl-6-(2-pyrazin-2-yl-5-m-tolyl-3H-imidazol-4-yl)-1H-benzotriazole;

n-[5-(3-methyl-3H-benzotriazol-5-yl)-4-m-tolyl-1H-imidazol-2-yl]-acetamide;

1-methyl-6-(2-pyridin-3-yl-5-m-tolyl-3H-imidazol-4-yl)-1H-benzotriazole;

1-isopropyl-6-(2-pyridin-3-yl-5-m-tolyl-3H-imidazol-4-yl)-1H-benzotriazole;

6-[4-(3-Chloro-4-fluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;

6-[5-(3-Chloro-4-fluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;

6-[4-(3-Chloro-4-fluoro-phenyl)-thiazol-5-yl]-1-isopropyl-1H-benzotriazole;

6-[3-(3-Chloro-4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-1-isopropyl-1H-benzotriazole;

6-[3-(3-Chloro-4-fluoro-phenyl)-5-methyl-isothiazol-4-yl]-1-isopropyl-1H-benzotriazole;

6-[3-(3-Chloro-4-fluoro-phenyl)-5-methyl-1H-pyrazol-4-yl]-1-isopropyl-1H-benzotriazole;

6-[2-(3-Chloro-4-fluoro-phenyl)-1H-pyrrol-3-yl]-1-isopropyl-1H-benzotriazole;

6-[5-(2-Chloro-4-fluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;

6-[4-(2-Chloro-4-fluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;

6-[4-(5-Chloro-2-fluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;

6-[5-(5-Chloro-2-fluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;

6-[5-(3-Chloro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;

6-[4-(3-Chloro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;

6-[4-(3,4-Difluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;

6-[5-(3,4-Difluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;

6-[5-(3,4-Difluoro-phenyl)-3H-imidazol-4-yl]-1-phenyl-1H-benzotriazole;

6-[4-(3,4-Difluoro-phenyl)-oxazol-5-yl]-1-phenyl-1H-benzotriazole;

6-[4-(3-Chloro-phenyl)-oxazol-5-yl]-1-phenyl-1H-benzotriazole;

6-[5-(3-Chloro-phenyl)-3H-imidazol-4-yl]-1-phenyl-1H-benzotriazole;

6-[5-(3-Chloro-4-fluoro-phenyl)-3H-imidazol-4-yl]-1-phenyl-1H-benzotriazole;

6-[4-(3-Chloro-4-fluoro-phenyl)-oxazol-5-yl]-1-phenyl-1H-benzotriazole;

6-[4-(3-Chloro-4-fluoro-phenyl)-oxazol-5-yl]-1-(2-chloro-phenyl)-1H-benzotriazole;

6-[5-(3-Chloro-4-fluoro-phenyl)-3H-imidazol-4-yl]-1-(2-chloro-phenyl)-1H-benzotriazole;

6-[5-(4-Fluoro-phenyl)-3H-imidazol-4-yl]-1-phenyl-1H-benzotriazole;

6-[4-(4-Fluoro-phenyl)-oxazol-5-yl]-1-phenyl-1H-benzotriazole;

1-Phenyl-6-(4-phenyl-oxazol-5-yl)-1H-benzotriazole;

6-[4-(4-Fluoro-3-methyl-phenyl)-oxazol-5-yl]-1-phenyl-1H-benzotriazole;

6-[4-(3-Chloro-4-fluoro-phenyl)-oxazol-5-yl]-1-isobutyl-1H-benzotriazole;

6-[5-(3-Chloro-4-fluoro-phenyl)-3H-imidazol-4-yl]-1-isobutyl-1H-benzotriazole;

6-[5-(2,5-Difluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;

6-[4-(2,5-Difluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;

6-[4-(3-Bromo-4-fluoro-phenyl)-oxazol-5-y]-1-isopropyl-1H-benzotriazole;

6-[5-(3-Bromo-4-fluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;

6-[5-(2,4-Difluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;

6-[4-(2,4-Difluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;

4-Phenyl-5-(3-phenyl-3H-benzotriazol-5-yl)-1l H-imidazole-2-carboxylicacid amide;

4-(4-Fluoro-phenyl)-5-(3-phenyl-3H-benzotriazol-5-yl)-1H-imidazole-2-carboxylicacid amide;

4-(3-Chloro-phenyl)-5-(3-phenyl-3H-benzotriazol-5-yl)-1H-imidazole-2-carboxylicacid amide;

4-(3-Chloro-phenyl)-5-(3-phenyl-3H-benzotriazol-5-yl)-1H-imidazole-2-carboxylicacid;

1-[4-(3-Chloro-phenyl)-5-(3-phenyl-3H-benzotriazol-5-yl)-1H-imidazol-2-yl]-ethanone;

1-[5-(3-Phenyl-3H-benzotriazol-5-yl)-4-m-tolyl-1H-imidazol-2-yl]-ethanone;

5-(3-Phenyl-3H-benzotriazol-5-yl)-4-m-tolyl-1H-imidazole-2-carboxylicacid;

5-(3-Phenyl-3H-benzotriazol-5-yl)-4-m-tolyl-1H-imidazole-2-carboxylicacid amide;

5-(3-Phenyl-3H-benzotriazol-5-yl)-4-m-tolyl-1H-imidazole-2-carboxylicacid methyl ester;

[5-(3-Phenyl-3H-benzotriazol-5-yl)-4-m-tolyl-1H-imidazol-2-yl]-urea;

[4-(3-Chloro-phenyl)-5-(3-phenyl-3H-benzotriazol-5-yl)-1H-imidazol-2-yl]-urea;

4-(3-Chloro-phenyl)-5-(3-phenyl-3H-benzotriazol-5-yl)-1H-imidazole-2-carboxylicacid methyl ester; and

5-[3-(2-Chloro-phenyl)-3H-benzotriazol-5-yl]-4-m-tolyl-1H-imidazole-2-carboxylic acid amide.

The present invention also includes isotopically-labelled compounds,which are identical to those recited in Formula I, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of thepresent invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labelled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of Formula I of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

The compounds of Formula I or a pharmaceutically acceptable salt thereofcan be used in the manufacture of a medicament for the prophylactic ortherapeutic treatment of any disease state in a human, or other mammal,which is exacerbated or caused by excessive or unregulated cytokineproduction by such mammal's cells, such as but not limited to monocytesand/or macrophages.

Compounds of Formula (I) are capable of inhibiting proinflammatorycytokines, such as IL-1, IL-6, IL-8, and TNF and are therefore of use intherapy. IL-1, IL-6, IL-8 and TNF affect a wide variety of cells andtissues and these cytokines, as well as other leukocyte-derivedcytokines, are important and critical inflammatory mediators of a widevariety of disease states and conditions. The inhibition of thesepro-inflammatory cytokines is of benefit in controlling, reducing andalleviating many of these disease states.

Accordingly, the present invention provides a method of treating acytokine mediated disease, which comprises administering an effectivecytokine-interfering amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

Certain compounds of Formula (I) are capable of inhibiting induciblepro-inflammatory proteins, such as COX-2, also referred to by many othernames such as prostaglandin endoperoxide synthase-2 (PGHS-2) and aretherefore of use in therapy. These proinflammatory lipid mediators ofthe cyclooxygenase (COX) pathway are produced by the inducible COX-2enzyme. Regulation, therefore of COX-2 which is responsible for theseproducts derived from arachidonic acid, such as prostaglandins, affect awide variety of cells and tissues. Expression of COX-1 is not effectedby compounds of Formula (I). This selective inhibition of COX-2 isaccepted as alleviating or sparing ulcerogenic liability associated withinhibition of COX-1 thereby inhibiting prostaglandins essential forcytoprotective effects. Thus inhibition of these pro-inflammatorymediators is of benefit in controlling, reducing and alleviating many ofthese disease states. Most notably these inflammatory mediators, inparticular prostaglandins, have been implicated in pain, such as in thesensitization of pain receptors, or edema. This aspect of painmanagement, therefore, includes treatment of neuromuscular pain,headache, cancer pain, and arthritis pain. Compounds of Formula (I), ora pharmaceutically acceptable salt thereof, are of use in therapy in ahuman, or other mammal, by inhibition of the synthesis of the COX-2enzyme.

Accordingly, the present invention provides a method of inhibiting thesynthesis of COX-2, which comprises administering an effective amount ofa compound of Formula (I) or a pharmaceutically acceptable salt thereof.The present invention also provides for a method of treatment in ahuman, or other mammal, by inhibition of the synthesis of the COX-2enzyme.

In particular, compounds of Formula (I) or a pharmaceutically acceptablesalt thereof are of use in the therapy of any disease state in a human,or other mammal, which is exacerbated by or caused by excessive orunregulated IL-1, IL-8 or TNF production by such mammal's cells, suchas, but not limited to, monocytes and/or macrophages.

Accordingly, in another aspect, this invention relates to a method ofinhibiting the production of IL-1 in a mammal in need thereof, whichcomprises administering to said mammal an effective amount of a compoundof Formula (I) or a pharmaceutically acceptable salt thereof.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These disease states include rheumatoid arthritis, osteoarthritis,meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed headinjury, stroke, endotoxemia and/or toxic shock syndrome, other acute orchronic inflammatory disease states such as the inflammatory reactioninduced by endotoxin or inflammatory bowel disease, tuberculosis,atherosclerosis, muscle degeneration, multiple sclerosis, cachexia, boneresorption, psoriatic arthritis, Reiter's syndrome, rheumatoidarthritis, gout, traumatic arthritis, rubella arthritis and acutesynovitis. Recent evidence also links IL-1 activity to diabetes,pancreatic p cells disease, and Alzheimer's disease.

Use of a p38 inhibitor for the treatment of p38 mediated disease states,can include, but is not limited to neurodegenerative diseases, such asAlzheimer's disease, Parkinson's disease and multiple sclerosis, etc. Ina further aspect, this invention relates to a method of inhibiting theproduction of TNF in a mammal in need thereof, which comprisesadministering to said mammal an effective amount of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof.

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions, sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, stroke, cerebral malaria, chronic obstructive pulmonarydisease, chronic pulmonary inflammatory disease, silicosis, pulmonarysarcoidosis, bone resorption diseases, such as osteoporosis, cardiac,brain and renal reperfusion injury, graft vs. host reaction, allograftrejections, fever and myalgias due to infection, such as influenza,(including HIV-induced forms), cerebral malaria, meningitis, ischemicand hemorrhagic stroke, cachexia secondary to infection or malignancy,cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS,or ARC (AIDS related complex), keloid formation, scar tissue formation,inflammatory bowel disease, Crohn's disease, ulcerative colitis andpyrosis.

Compounds of Formula (I) are also useful in the treatment of viralinfections, where such viruses are sensitive to upregulation by TNF orwill elicit TNF production in vivo. The viruses contemplated fortreatment herein are those that produce TNF as a result of infection, orthose which are sensitive to inhibition, such as by decreasedreplication, directly or indirectly, by the TNF inhibiting-compounds ofFormula (I). Such viruses include, but are not limited to HIV-1, HIV-2and HIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpesgroup of viruses, such as but not limited to, Herpes Zoster and HerpesSimplex. Accordingly, in a further aspect, this invention relates to amethod of treating a mammal afflicted with a human immunodeficiencyvirus (HIV) which comprises administering to such mammal an effectiveTNF inhibiting amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

Compounds of Formula (I) may also be used in association with theveterinary treatment of mammals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment, inanimals include disease states such as those noted above, but inparticular viral infections. Examples of such viruses include, but arenot limited to, lentivirus infections such as, equine infectious anemiavirus, caprine arthritis virus, visna virus, or maedi virus orretrovirus infections, such as but not limited to felineimmunodeficiency virus (FIV), bovine immunodeficiency virus, or canineimmunodeficiency virus or other retroviral infections.

The compounds of Formula (I) may also be used topically in the treatmentof topical disease states mediated by or exacerbated by excessivecytokine production, such as by IL-1 or TNF respectively, such asinflamed joints, eczema, contact dermatitis psoriasis and otherinflammatory skin conditions such as sunburn; inflammatory eyeconditions including conjunctivitis; pyrosis, pain and other conditionsassociated with inflammation. Periodontal disease has also beenimplemented in cytokine production, both topically and systemically.Hence, the use of compounds of Formula (I) to control the inflammationassociated with cytokine production in such peroral diseases such asgingivitis and periodontitis is another aspect of the present invention.

Compounds of Formula (I) have also been shown to inhibit the productionof IL-8 (Interleukin-8, NAP). Accordingly, in a further aspect, thisinvention relates to a method of inhibiting the production of IL-8 in amammal in need thereof which comprises administering, to said mammal aneffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

There are many disease states in which excessive or unregulated IL-8production is implicated in exacerbating and/or causing the disease.These diseases are characterized by massive neutrophil infiltration suchas, psoriasis, inflammatory bowel disease, asthma, cardiac and renalreperfusion injury, adult respiratory distress syndrome, thrombosis andglomerulonephritis. All of these diseases are associated with increasedIL-8 production, which is responsible for the chemotaxis of neutrophilsinto the inflammatory site. In contrast to other inflammatory cytokines(IL-1, TNF, and IL-6), IL-8 has the unique property of promotingneutrophil chemotaxis and activation. Therefore, the inhibition of IL-8production would lead to a direct reduction in the neutrophilinfiltration.

The compounds of Formula (I) are administered in an amount sufficient toinhibit a cytokine, in particular IL-1, IL-6, IL-8 or TNF, productionsuch that it is regulated down to normal levels, or in some case tosubnormal levels, so as to ameliorate or prevent the disease state.Abnormal levels of IL-1, IL-6, IL-8 or TNF, for instance in the contextof the present invention, constitute: (i) levels of free (not cellbound) IL-1, IL-6, IL-8 or TNF greater than or equal to 1 picogram perml; (ii) any cell associated IL-1, IL-6, IL-8 or TNF; or (iii) thepresence of IL-1, IL-6, IL-8 or TNF mRNA above basal levels in cells ortissues in which IL-1, IL-6, IL-8 or TNF, respectively, is produced.

The discovery that the compounds of Formula (I) are inhibitors ofcytokines, specifically IL-1. IL-6, IL-8 and TNF is based upon theeffects of the compounds of Formula (I) on the production of the IL-1,IL-8 and TNF in in vitro assays which are described herein or are wellknown to those skilled in the art.

As used herein, the term “inhibiting the production of IL-1 (IL-6, IL-8or TNF)” refers to:

a) a decrease of excessive in vivo levels of the cytokine (IL-1, IL-6,IL-8 or TNF) in a human to normal or sub-normal levels by inhibition ofthe in vivo release of the cytokine by all cells, including but notlimited to monocytes or macrophages;

b) a down regulation, at the genomic level, of excessive in vivo levelsof the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal orsub-normal levels;

c) a down regulation, by inhibition of the direct synthesis of thecytokine (IL-1, IL-6, IL-8 or TNF) as a postranslational event to normalor sub-normal levels; or

d) a down regulation, at the translational level, of excessive in vivolevels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal orsub-normal levels.

As used herein, the term “TNF mediated disease or disease state” refersto any and all disease states in which TNF plays a role, either byproduction of TNF itself, or by TNF causing another monokine to bereleased, such as but not limited to IL-1, IL-6 or IL-8. A disease statein which, for instance, IL-1 is a major component, and whose productionor action, is exacerbated or secreted in response to TNF, wouldtherefore be considered a disease state mediated by TNF.

As used herein, the term “cytokine” refers to any secreted polypeptidethat affects the functions of cells and is a molecule, which modulatesinteractions between cells in the immune, inflammatory or hematopoieticresponse. A cytokine includes, but is not limited to, monokines andlymphokines, regardless of which cells produce them. For instance, amonokine is referred to as being produced and secreted by a mononuclearcell, such as a macrophage and/or monocyte. Many other cells howeveralso produce monokines, such as natural killer cells, fibroblasts,basophils, neutrophils, endothelial cells, brain astrocytes, bone marrowstromal cells, epidermal keratinocytes and B-lymphocytes. Lymphokinesare generally referred to as being produced by lymphocyte cells.Examples of cytokines include, but are not limited to Interleukin-1(IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor NecrosisFactor-alpha (TNF-α) and Tumor Necrosis Factor beta (TNF-β).

As used herein, the term “cytokine interfering” or “cytokine suppressiveamount” refers to an effective amount of a compound of Formula (I) whichwill cause a decrease in the in vivo levels of the cytokine to normal orsub-normal levels, when given to a patient for the treatment of adisease state which is exacerbated by, or caused by, excessive orunregulated cytokine production.

As used herein, the cytokine referred to in the phrase “inhibition of acytokine for use in the treatment of a HIV-infected human” is a cytokinewhich is implicated in (a) the initiation and/or maintenance of T cellactivation and/or activated T cell-mediated HIV gene expression and/orreplication and/or (b) any cytokine-mediated disease associated problemsuch as cachexia or muscle degeneration.

As TNF-β (also known as lymphotoxin) has close structural homology withTNF-α (also known as cachectin) and since each induces similar biologicresponses and binds to the same cellular receptor, both TNF-α and TNF-βare inhibited by the compounds of the present invention and thus areherein referred to collectively as “TNF” unless specifically delineatedotherwise.

A relatively new member of the MAP kinase family, alternatively termedCSBP, p38 or RK, has been identified by several laboratories [See Lee etal., Nature, Vol. 300, n(72), 739-746 (1994)]. Activation of thisprotein kinase via dual phosphorylation has been observed in differentcell systems upon stimulation by a wide spectrum of stimuli, such asphysicochemical stress and treatment with lipopolysaccharide orproinflammatory cytokines such as interleukin-1 and tumor necrosisfactor. The cytokine biosynthesis inhibitors, of the, present invention,compounds of Formula (i) have been determined to be potent and selectiveinhibitors of CSBP/p38/RK kinase activity, These inhibitors are of aidin determining the signaling pathways involvement in inflammatoryresponses. In particular, a definitive signal transduction pathway canbe prescribed to the action of lipopolysaccharide in cytokine productionin macrophages. In addition to those diseases already noted herein,treatment of stroke, neurotrauma/CNS head injury, cardiac, brain andrenal reperfusion injury, thrombosis, glomerulonephritis, diabetes andpancreatic p cells, multiple sclerosis, muscle degeneration, eczema,psoriasis, sunburn, and conjunctivitis are also included.

The cytokine inhibitors were subsequently tested in a number of animalmodels for anti-inflammatory activity. Model systems were chosen thatwere relatively insensitive to cyclooxygenase inhibitors in order toreveal the unique activities of cytokine suppressive agents. Theinhibitors exhibited significant activity in many such in vivo studies.Most notable are its effectiveness in the collagen-induced arthritismodel and inhibition of TNF production in the endotoxic shock model. Inthe latter study, the reduction in plasma level of TNF correlated withsurvival and protection from endotoxic shock related mortality. Also ofgreat importance are the compound's effectiveness in inhibiting boneresorption in a rat fetal long bone organ culture system. Griswold etal., (1988) Arthritis Rheum. 31:1406-1412; Badger, et al., (1989) Circ.Shock 27, 51-61, Votta et al., (1994) in vitro. Bone 15, 533-538; Lee etal., (1993.). B Ann. N.Y. Acad. Sci. 696, 149-170.

It is also recognized that both IL-6 and IL-8 are produced duringrhinovirus (HRV) infections and contribute to the pathogenesis of commoncold and exacerbation of asthma associated with HRV infection (Turner etal., (1998), Clin. Infec. Dis., Vol. 26, p. 840; Teren et al. (1997),Am. J. Respir. Crit. Care Med., Vol. 155, p. 1362; Grunberg et al.(1997), Am. J. Respir. Crit. Care Med., Vol. 156, p. 609 and Zhu et al.,J. Clin. Invest. (1996), Vol. 97, p 421). It has also been demonstratedin vitro that infection of pulmonary epithelial cells with HRV resultsin production of IL-6 and IL-8 (Subauste et al., J. Clin. Invest.(1995), Vol. 96, p. 549). Epithelial cells represent the primary site ofinfection of HRV. Therefore, another aspect of the present invention isa method of treatment to reduce inflammation associated with arhinovirus infection, not necessarily a direct effect of the virusitself.

Another aspect of the present invention involves the novel use of thesep38/cytokine inhibitors for the treatment of chronic inflammatory orproliferative or angiogenic diseases, which are caused by excessive, orinappropriate angiogenesis.

Chronic diseases, which have an inappropriate angiogenic component, arevarious ocular neovascularizations, such as diabetic retinopathy andmacular degeneration. Other chronic diseases, which have an excessive orincreased proliferation of vasculature, are tumor growth and metastasis,atherosclerosis and certain arthritic conditions. Therefore, cytokineinhibitors will be of utility in the blocking of the angiogeniccomponent of these disease states.

The term “excessive or increased proliferation of vasculatureinappropriate angiogenesis” as used herein includes, but is not limitedto, diseases which are characterized by hemangiomas and ocular diseases.

The term “inappropriate angiogenesis” as used herein includes, but isnot limited to, diseases which are characterized by vesicleproliferation with accompanying tissue proliferation, such as occurs incancer, metastasis, arthritis and atherosclerosis.

This invention also encompasses methods of treating or preventingdisorders that can be treated or prevented by the inhibition of ERKIMAPin a mammal, preferably a human, comprising administering to said mammalan effective amount of a compound of the formula 1.

Accordingly, the present invention provides a method of treating a p38kinase mediated disease in a mammal in need thereof, preferably a human,which comprises administering to said mammal, an effective amount of acompound of Formula (I) or a pharmaceutically acceptable salt thereof.

Preferred p38 mediated diseases for treatment include, but are notlimited to psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis,gout, traumatic arthritis, rubella arthritis and acute synovitis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions, sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, Alzheimer's disease, stroke,ischemic and hemorrhagic stroke, neurotrauma/closed head injury, asthma,adult respiratory distress syndrome, chronic obstructive pulmonarydisease, cerebral malaria, meningitis, chronic pulmonary inflammatorydisease, silicosis, pulmonary sarcostosis, bone resorption disease,osteoporosis, restenosis, cardiac reperfusion injury, brain and renalreperfusion injury, chronic renal failure, thrombosis,glomerulonephritis, diabetes, diabetic retinopathy, maculardegeneration, graft vs. host reaction, allograft rejection, inflammatorybowel disease, Crohn's disease, ulcerative colitis, neurodegenerativedisease, multiple sclerosis, muscle degeneration, diabetic retinopathy,macular degeneration, tumor growth and metastasis, angiogenic disease,rhinovirus infection, peroral disease, such as gingivitis andperiodontitis, eczema, contact dermatitis, psoriasis, sunburn, andconjunctivitis.

The term “treating”, as used herein, refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies, or one or more symptoms of such disorder orcondition. The term “treatment”, as used herein, refers to the act oftreating, as “treating” is defined immediately above.

This invention also encompasses pharmaceutical compositions for thetreatment of a condition selected from the group consisting ofarthritis, psoriatic arthritis, Reiter's syndrome, gout, traumaticarthritis, rubella arthritis and acute synovitis, rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions, sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, Alzheimer's disease, stroke,neurotrauma, asthma, adult respiratory distress syndrome, cerebralmalaria, chronic pulmonary inflammatory disease, silicosis, pulmonarysarcoidosis, bone resorption disease, osteoporosis, restenosis, cardiacand renal reperfusion injury, thrombosis, glomerulonephritis, diabetes,graft vs. host reaction, allograft rejection, inflammatory boweldisease, Crohn's disease, ulcerative colitis, multiple sclerosis, muscledegeneration, eczema, contact dermatitis, psoriasis, sunburn, orconjunctivitis shock in a mammal, including a human, comprising anamount of a compound of formula I effective in such treatment and apharmaceutically acceptable carrier.

This invention also encompasses pharmaceutical compositions for thetreatment of a condition which can be treated by the inhibition ofERK/MAP kinase in a mammal, including a human, comprising an amount of acompound of formula I effective in such treatment and a pharmaceuticallyacceptable carrier.

This invention also encompasses pharmaceutical compositions for thetreatment of a condition which can be treated by the inhibition of p38kinase in a mammal, including a human, comprising an amount of acompound of formula I effective in such treatment and a pharmaceuticallyacceptable carrier.

This invention also encompasses pharmaceutical compositions containingprodrugs of compounds of the formula 1. Compounds of formula I havingfree amino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues which are covalently joined through peptide bonds to freeamino, hydroxy or carboxylic acid groups of compounds of formula 1. Theamino acid residues include the 20 naturally occurring amino acidscommonly designated by three letter symbols and also include,4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amidesand alkyl esters which are covalently bonded to the above substituentsof formula I through the carbonyl carbon prodrug sidechain.

The present invention also encompasses sustained release compositions.

The present invention also relates to processes of preparing thecompounds of formula I and intermediates used in such processes.

One of ordinary skill in the art will appreciate that the compounds ofthe invention are useful in treating a diverse array of diseases. One ofordinary skill in the art will also appreciate that when using thecompounds of the invention in the treatment of a specific disease thatthe compounds of the invention may be combined with various existingtherapeutic agents used for that disease.

For the treatment of rheumatoid arthritis, the compounds of theinvention may be combined with agents such as TNF-α inhibitors such asanti-TNF monoclonal antibodies (such as Remicade, CDP-870 and D₂E₇) andTNF receptor immunoglobulin molecules (such as Enbrel®), COX-2inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib andetoricoxib) low dose methotrexate, leflunomide, hydroxychloroquine,d-penicillamine, auranofin or parenteral or oral gold.

The compounds of the invention can also be used in combination withexisting therapeutic agents for the treatment of osteoarthritis.Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents (hereinafter NSAID's) such as piroxicam,diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin, COX-2 inhibitors such as celecoxib,valdecoxib, rofecoxib and etoricoxib, analgesics and intraarticulartherapies such as corticosteroids and hyaluronic acids such as hyalganand synvisc.

The compounds of the present invention may also be used in combinationwith anticancer agents such as endostatin and angiostatin or cytotoxicdrugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol,taxotere and alkaloids, such as vincristine, farnesyl transferaseinhibitors, VegF inhibitors, and antimetabolites such as methotrexate.

The compounds of the invention may also be used in combination withantiviral agents such as Viracept, AZT, aciclovir and famciclovir, andantisepsis compounds such as Zovant, tifacogin, NOX-100 and GR270773.

The compounds of the present invention may also be used in combinationwith cardiovascular agents such as calcium channel blockers, lipidlowering agents such as statins, fibrates, beta-blockers, Aceinhibitors, Angiotensin-2 receptor antagonists and platelet aggregationinhibitors.

The compounds of the present invention may also be used in combinationwith CNS agents such as antidepressants (such as sertraline),anti-Parkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOBinhibitors such as selegine and rasagiline, comP inhibitors such asTasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists,Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitricoxide synthase), and anti-Alzheimer's drugs such as donepezil, tacrine,COX-2 inhibitors, propentofylline or metryfonate.

The compounds of the present invention may also be used in combinationwith osteoporosis agents such as roloxifene, droloxifene, lasofoxifeneor fosomax and immunosuppressant agents such as FK-506 and rapamycin.

BRIEF DESCRIPTION OF DRAWING

FIG. 1 illustrates MAP Kinase cascade.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the formula I may be prepared according to the followingreaction schemes and discussion. Unless otherwise indicated, m, n, p, s,B, R² through R¹⁶ and Het and structural formula I in the reactionschemes and discussion that follow are as defined above.

Scheme 1 refers to the preparation of compounds of the formula 1.Referring to Scheme 1, a compound of the formula I, wherein(R³)_(s)-phenyl-Het is (c) or (f), can be prepared from compounds of theformula II by reaction with an aminating reagent. Suitable aminatingreagents include hydrazines of the formula H₂N—NH—R⁷, in a polarsolvent. Suitable solvents include alcohols such as ethanol, propanol orbutanol or mixtures of alcohols and acetic acid, preferably ethanol. Theaforesaid reaction is conducted at a temperature of about 10° C. toabout 30° C., preferably at about 22° C., for a period from about 1 hourto about 7 hours, preferably about 3 hours.

The compound of formula II is prepared from a compound of formula VI byreaction with an acetal, such as dimethylformamide—dimethylacetal, at atemperature of about 60° C. to about 90° C., preferably about 80° C. fora period from about 1 hour to about 6 hours, preferably about 3 hours.

Alternatively, compounds of the formula I, wherein (R³)_(s)-phenyl-Hetis (c) or (f), can be prepared from compounds of the formula III byreaction with an aminating reagent such as H₂N—NH—R⁷ according tomethods analogous to the conversion of compounds of formula II toformula I, above.

The compound of formula III is prepared from a compound of formula VI byreaction with an isothiocyanate. Suitable isothiocyanates includecompounds of the formula R⁴—N═C═S. Reactions with isothiocyanates arefacilitated by the addition of a base, such as sodium hydride, lithiumdiisopropylamide or other suitable strong bases. Suitable solvents forthe aforesaid reaction include pyridine, N,N-dimethylformamide ortetrahydrofuran, preferably pyridine. The aforesaid reaction isperformed from a period of about 0.5 hour to about 4 hours at atemperature of about 0° C. to about 30° C. The deprotonation reactionwith above said bases is followed by the addition of a suitableisothiocyanate and is performed for a period from about 10 minutes toabout 20 hours, at a temperature of about 0° C. to about 30° C.,preferably about 22° C. for a period from about 0.5 hour to about 24hours.

Compounds of the formula I, wherein (R³)_(s)-phenyl-Het is (b), can beprepared from compounds of the formula IV, by reaction with an aldehydeof the formula R⁶—(C═O)H in the presence of an ammonia source andcuprous acetate and a polar solvent. Suitable ammonia sources includeammonium trifluoroacetate, ammonia, and ammonium acetate, preferablyammonium acetate. The aforesaid reaction can be run neat or in thepresence of a solvent such as alcohols (methanol, ethanol or butanol)and acetic acid. The aforesaid reaction can be run at a temperature fromabout 20° C. to about 80° C. for a period from about 15 minutes to about4 hours, preferably neat conditions at about 60° C. for about 2 hours.

Compounds of the formula I, wherein (R³)_(s)-phenyl-Het is (d) can beprepared from compounds of the formula IV, by reaction with an acylatingreagent of the formula R⁶(C═O)—L, wherein L is a leaving group such ashalo or anhydrido, using method well known to those skilled in the art.The acyl derivative, so formed, is converted to the compound of formulaI by cyclodehydration in the presence of a source of ammonia. Suitablesolvents include acetic acid and tetrahydrofuran. The aforesaid reactioncan be run at a temperature from about 22° C. to about 80° C.,preferably 50° C., for a period from about 1 hour to about 24 hours,preferably 2 hours.

The compound of formula IV is prepared from a compound of formula V byreaction with sodium methoxide, or sodium ethoxide, or sodiumtert-butoxide, preferably sodium methoxide, in an alcohol solvent, suchas methanol, ethanol, isopropanol, preferably methanol. The aforesaidreaction can be conducted at a temperature of about 0° C. to about 30°C., preferably at about 22° C., for a period of time from 15 minutes toabout 3 hours, preferably about 30 minutes. The aforesaid reaction isfollowed by an aqueous acidic work-up.

The compound of formula V is prepared from a compound of formula VI byreaction with bromine (Br₂) in a polar solvent. Suitable solventsinclude acetic acid, chloroform or methylene chloride, preferably aceticacid. The aforesaid reaction is conducted at a temperature of about 0°C. to about 30° C. preferably at about 22° C. (room temperature) for aperiod from about 10 minutes to about 4 hours, preferably about 30minutes.

Compounds of the formula I, wherein (R³)_(s)-phenyl-Het is (a), can beprepared from compounds of the formula VII, by reaction with an ammoniasource and cuprous acetate and a polar solvent. Suitable ammonia sourcesinclude ammonium trifluoroacetate, ammonia, and ammonium acetate,preferably ammonium acetate. The aforesaid reaction can be run neat orin the presence of a solvent such as alcohols (methanol, ethanol orbutanol) and acetic acid. The aforesaid reaction can be run at atemperature from about 20° C. to about 80° C. for a period from about 15minutes to about 4 hours, preferably neat conditions at about 60° C. forabout 2 hours.

Alternatively, compounds of formula I (g) and (h) can be prepared fromcompounds of formula VI according to methods described in the literature(Gauthier, J. Y.; Leblanc, Y.; Black, C.; Chan, C. -C.; Cromlish, W. A.;Gordon, R.; Kennedey, B. P.; Lau, C. K.; Leger, S.; Wang, Z.; Ethier,D.; Guay, J.; Mancini, J.; Riendeau, D.; Tagari, P.; Vickers, P.; Wong,E.; Xu, L.; Prasit, P. Bioorg. Med. Chem. Lett. 1996, 6, 87-92).

The compound of formula VII is prepared from a compound of formula VI byreaction with a reagent of the formula

wherein L is a leaving group such as chloro, bromo, iodo or mesylate, inthe presence of a base and a solvent. Suitable bases include sodiumhydride (NaH) and n-butyllithium. Suitable solvents includetetrahydrofuran (THF) and dimethyl formamide (DMF). The aforesaidreaction can be conducted at a temperature from about −30° C. to aboutthe reflux temperature of the solvent, for a period of about 5 minutesto about 24 hours.

The compound of formula VI is prepared according to the methods ofDavies, I. W.; Marcoux, J. -F.; Corley, E. G.; Journet, M.; Cai, D. -W.;Palucki, M.; Wu, J.; Larsen, R. D.; Rossen, K.; Pye, P. J.; DiMichele,L.; Dormer, P.; Reider, P. J.; J. Org. Chem., Vol. 65, pp. 8415-8420(2000). The compound of formula VIII is prepared by methods well knownto those skilled in the art.

Scheme 2 refers to an alternate preparation of compounds of formula I,wherein (R³)_(s)-phenyl-Het is (b), from compounds of the formula XIV.Compounds of the formula XIV can be prepared by the methods of Scheme 4.

Referring to Scheme 2, a compound of the formula I, wherein(R³)_(s)-phenyl-Het is a group of the formula (b), can be prepared froma compound of the formula X by reaction with a compound of the formula

wherein R⁵ is hydrogen, in the presence of a polar solvent. Suitablesolvents include dimethyl formamide, chloroform, DMSO, THF and ethanol,preferably dimethylformamide. The aforesaid reaction is conducted at atemperature of about 15° C. to about 80° C., preferably about 60° C.,for a period from about 4 hours to about 4 days, preferably 4 hours.

Alternatively, a compound of the formula I, wherein (R³)_(s)-phenyl-Hetis a group of the formula (b), can be prepared from a compound offormula XII by reaction with R⁶—(C═O)H in the presence of an ammoniasource. Suitable ammonia sources include ammonium trifluoroacetate,ammonia, and ammonium acetate, preferably ammonium acetate. Theaforesaid reaction can be run neat or in the presence of a solvent suchas alcohols (methanol, ethanol or butanol) and acetic acid. Theaforesaid reaction can be run at a temperature from about 20° C. toabout 80° C. for a period from about 15 minutes to about 4 hours,preferably neat conditions at about 60° C. for about 2 hours.

The compound of formula XII is prepared from a compound of the formulaXIII by reaction with an oxidizing reagent in a polar protic solvent.Suitable oxidizing reagents include copper acetate,pyridiniumchlorochromate (PCC) and tetrapropylammoniumperuthenate/N-methyl morpholine-N-oxide (TPAP/NMO), preferably cuprousacetate. Suitable solvents include acetic acid. The aforesaid reactioncan be run neat or in the presence of a solvent such as alcohols(methanol, ethanol or butanol) and acetic acid. The aforesaid reactioncan be run at a temperature from about 20° C. to about 80° C. for aperiod from about 15 minutes to about 4 hours, preferably neatconditions at about 60° C. for about 2 hours.

Alternatively, a compound of the formula I, wherein (R³)_(s)-phenyl-Hetis a group of the formula (b), can be prepared from a compound offormula XIII, by reaction with an aldehyde of the formula R⁶—(C═O)—H inthe presence of cuprous acetate and an ammonia source according tomethods analogous to those for the conversion of compounds of formula IVto formula I in Scheme 1.

The compound of formula XIII is prepared from a compound of the formulaX by reaction with a methoxide such as described in Scheme 1 for thepreparation of compounds of formula IV from compounds of formula V.

The compound of formula X is prepared from a compound of the formula XIVby reaction with Br₂ in a polar solvent. Suitable solvents includeacetic acid, chloroform or methylene chloride, preferably acetic acid.The aforesaid reaction is conducted at a temperature of about 0° C. toabout 30° C. preferably at about 22° C. (room temperature) for a periodfrom about 10 minutes to about 4 hours, preferably about 30 minutes.

Scheme 3 refers to an alternate preparation of compounds of formula I,wherein (R³)_(s)-phenyl-Het is a group of the formula (b) or (d) and R⁶is hydrogen. Referring to Scheme 3, a compound of formula I, wherein(R³)_(s)-phenyl-Het is of the formula (d) and R⁶ is hydrogen, isprepared from a compound of formula XVII by reaction with an isocyanideof formula

in the presence of a base. Suitable bases include potassium carbonate,triethylamine, and piperazine, preferably potassium carbonate. Suitablesolvents include polar solvents such as tetrahydrofuran, orN,N-dimethylformamide, preferably in N,N-dimethylformamide. Theaforesaid reaction may be run at a temperature between about 22° C. andabout 70° C., preferably at about 22° C. for a period from about 2 hoursto about 4 hours, followed by about 6 hours to about 10 hours at atemperature of about 70° C.

Compounds of formula I, wherein (R³)_(s)-phenyl-Het is of the formula(b) and R⁶ is hydrogen, can be prepared in an analogous way by firstpreparation of the intermediate imine of formula XV by reaction ofcompounds of formula XVII with a suitable amine of the formula NH₂R⁵under dehydrating conditions. Such conditions include the treatment ofcompounds of formula XVII and an amine NH₂R⁵ in a solvent such astetrahydrofuran or dichloromethane with a dehydrating agent such asanhydrous magnesium sulfate or molecular sieves. Alternatively, theimine of formula XV can be prepared and subsequently reacted in anaqueous media as described in the literature: (Sisko, J.; Kassik, A. J.;Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A.; J. Org. Chem., 65,1516-1524 (2000)). Reactions of imines of formula XV with suitableisocyanides of formula XVI are conducted at about 22° C. for a timeperiod from about 1 day to about 21 days, preferably about 1 day.

A compound of formula XVII is prepared from a compound of formula XXIIIin Scheme 4.

Scheme 4 refers to an alternate preparation of compounds of the formulaI, wherein (R³)_(s)-phenyl-Het is a group of the formula (b). Referringto Scheme 4, compounds of the formula I are prepared from compounds ofthe formula XVIII by reaction with an ammonia source. Suitable ammoniasources include ammonium trifluoroacetate, ammonia, and ammoniumacetate, preferably ammonium trifluoroacetate. The aforesaid reactioncan be run neat or in the presence of a solvent such as alcohols(methanol, ethanol or butanol) and acetic acid. The aforesaid reactioncan be run at a temperature from about 60° C. to about 150° C. for aperiod from about 15 minutes to about 3 hours, preferably neatconditions at about 150° C. for about 1 hour.

The compound of formula XVIII is prepared form a compound of formula XIXby reaction with an oxidizing reagent such as N-methyl morpholineN-oxide/TPAP, Dess-Martin reagent, PCC or oxalyl chloride-DMSO,preferably N-methyl morpholine N-oxide/TPAP. Suitable solvents for theaforesaid reaction include methylene chloride, chloroform, THF ordichloromethane. The aforesaid reaction is conducted at a temperaturefrom about 10° C. to about 30° C. for a time from about 15 minutes toabout 3 hours, preferably about 1 hour.

The compound of formula XIX is prepared from a compound of the formulaXX by reaction with an acylating reagent of the formula,

wherein L is a leaving group, and a base. Suitable bases includetriethylamine, Hunig's base, or DBU, preferably triethylamine. Suitableleaving groups include Cl, Br or activated acids. Suitable solvents forthe aforesaid reaction include methylene chloride, dimethyl formamide,THF or DMF, and mixtures thereof, preferably methylene chloride. Theaforesaid reaction is conducted at a temperature from about 10° C. toabout 30° C. preferably about 22° C. (room temperature) for a periodfrom about 1 hour to about 6 hours preferably about 1 hour.

The compound of the formula XX is prepared form a compound of formulaXXII by reaction with a reducing agent. Reducing agents are well knownto those skilled in the art. For example, reduction of the double bondmay be effected with hydrogen gas (H₂), using catalysts such aspalladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO₄),platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride(Wilkinson's catalyst), in an appropriate solvent such as methanol,ethanol, THF, dioxane or ethyl acetate, at a pressure from about 1 toabout 5 atmospheres and a temperature from about 10° C. to about 60° C.,as described in Catalytic Hydrogenation in Organic Synthesis, PaulRylander, Academic Press Inc., San Diego, 31-63 (1979). The followingconditions are preferred: Pd on carbon, methanol at 25° C. and 50 psi ofhydrogen gas pressure.

The compound of the formula XXII is prepared from a compound of formulaXIV by reaction with a base or acid and an alkyl nitrite. Suitablenitrites include n-butyl nitrite, t-butyl, or iso-amyl, preferablyn-butyl nitrite. Suitable bases include sodium ethoxide, sodiummethoxide or potassium t-butoxide, preferably sodium ethoxide. Suitablesolvents for the aforesaid reaction include alcohols (such as methanol,ethanol, propanol or butanol) or DMSO, preferably ethanol. The aforesaidreaction is conducted at a temperature of about-10° C. to about 5° C.preferably 0° C., for a period from about 1 hour to about 48 hours,preferably about 24 hours.

The compound of the formula XIV is prepared from a compound of theformula XXIII by reaction with a Grignard reagent of the formula(R³)-phenyl-CH₂-M, wherein M is magnesium chloride or magnesium bromide.Suitable solvents for the aforesaid reaction are ethers (such asdimethyl ether THF, DME or dioxane), preferably THF. The aforesaidreaction is conducted at a temperature from about 0° C. to about 30° C.,preferably at about 22° C. (room temperature), for a period from about 1hour to about 48 hours, preferably about 6 hours.

Compounds of the formula XXIII can be made according to the methods ofScheme 6.

Scheme 5 refers to the preparation of compounds of the formula I,wherein (R³)_(s)-phenyl-Het is a group of the formula (e). Referring toScheme 5, a compound of the formula I can be prepared from compound offormula XXIV by reaction with a hydroxylamine (preferably a salt thereofsuch as the hydrochloride salt), and a base. Suitable bases includepyridine or a trialkylamine, preferably pyridine. Suitable solventsinclude N,N-dimethylformamide, tetrahydrofuran or pyridine, preferablypyridine. The aforesaid reaction is conducted at a temperature fromabout 0° C. to about 100° C., preferably at about 60° C., for a periodfrom about 1 hour to about 48 hours, preferably about 20 hours.

The compound of formula XXIV can be prepared from a compound of formulaXXV by reaction with an ester of the formula (R³)_(s)-phenyl-CO₂P¹,wherein P¹ is methyl or ethyl, in the presence of a base and a solvent.Suitable bases include sodium hydride, lithium diisopropylamide, orsodium alkoxides, preferably sodium ethoxide. Suitable solvents includealcohols such as methanol, ethanol, propanol, butanol, ortetrahydrofuran, preferably ethanol. The aforesaid reaction is conductedat a temperature from about 23° C. to about 65° C., preferably at about50° C., for a period from about 2 hours to about 24 hours, preferablyabout 20 hours.

The compound of formula XXV can be made by methods well known to thoseof ordinary skill in the art and in Scheme 7 from compounds of formulaXXXI by reaction with a halogenating reagent followed by reaction with anitrite according to methods well known to those of ordinary skill inthe art.

Scheme 6 refers to the preparation of compounds of the formula XVII andXXIII which are intermediates for the preparation of compounds offormula I in Schemes 3 and 4, respectfully. Referring to Scheme 6, acompound of the formula XVII is prepared from a compound of formulaXXIII by reaction with a reducing agent, such as diisobutylaluminumhydride (DiBAl) in toluene, in a solvent, such as tetrahydrofuran (THF).The aforesaid reaction may be run at a temperature from about −78° C. toroom temperature for a period from about one to about five hours.

The compound of formula XXIII is prepared from a compound of formulaXXVI by reaction with a suitable activating agent and a compound of theformula,

and a base. Suitable activating agents include thionyl chloride, EDCland DCC, preferably oxalyl chloride. Suitable bases includetriethylamine, Hunig's base, or DBU, preferably triethylamine. Suitablesolvents for the aforesaid reaction include methylene chloride, dimethylformamide, THF or DMF, and mixture thereof, preferably methylenechloride. The aforesaid reaction is conducted at a temperature fromabout 0° C. to about 30° C. preferably about 22° C. (room temperature)for a period from about 6 hours to about 48 hours preferably about 12hours.

The compound of formula XXVI is prepared from a compound of formulaXXVIII by reaction with sodium nitrite under acidic conditions. Suitableacids include hydrochloric acid. The aforesaid reaction is conducted ata temperature from about 0° C. to about 100° C., preferably about 22°C., for a period from about 1 hour to about 3 hours, preferably about 2hours.

The compound of formula XXVIII is prepared from a compound of formulaXXIX by reaction with a reducing agent. Reducing agents are well knownto those skilled in the art. For example, reduction of the double bondmay be effected with hydrogen gas (H₂), using catalysts such aspalladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO₄),platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride(Wilkinson's catalyst), in an appropriate solvent such as methanol,ethanol, THF, dioxane or ethyl acetate, at a pressure from about 1 toabout 5 atmospheres and a temperature from about 10° C. to about 60° C.,as described in Catalytic Hydrogenation in Organic Synthesis, PaulRylander, Academic Press Inc., San Diego, 31-63 (1979). The followingconditions are preferred: Pd on carbon, methanol at 25° C. and 50 psi ofhydrogen gas pressure.

The compound of formula XXIX can be prepared from a compound of formulaXXX by reaction with an amine of the formula R²NH₂. Suitable solventsinclude an excess of the amine reactant (neat), glyme, and toluene,preferably neat. The aforesaid reaction is conducted at a temperaturefrom about 70° C. to about 120° C., preferably 100° C., for a periodfrom about 10 minutes to about 1 hour, preferably about 30 minutes.

The compound of the formula XXX is commercially available or can beprepared by methods well known to those skilled in the art.

Scheme 7 refers to an alternate preparation of compounds of the formulaXVII which are intermediates useful in the preparation of compounds offormula I in Scheme 3. Referring to Scheme 7, a compound of the formulaXVII is prepared from a compound of formula XXXI by reaction with anoxidizing reagent such as N-methyl morpholine N-oxide/TPAP, Dess-Martinreagent, PCC or oxalyl chloride-DMSO, preferably oxalyl chloride-DMSO.Suitable solvents for the aforesaid reaction include methylene chloride,chloroform, THF or dichloromethane. The aforesaid reaction is conductedat a temperature from about −78° C. to about 22° C. for a time fromabout 15 minutes to about 3 hours, preferably about 1 hour.

The compound of the formula XXXI is prepared from a compound of theformula XXXII by reaction with a reducing reagent. Suitable reducingagents include lithium borohydride, sodium borohydride (NaBH₄), sodiumcyanoborohydride (NaCNBH₃), lithium aluminum hydride (LiAlH₄) and boranein THF (BH₃THF). Suitable solvents include methanol, ethanol, THF,diethyl ether, dioxane and tetrahydrofuran. The aforesaid reaction isconducted at a temperature from about 0° C. to about 70° C., preferably65° C., for a period from about 10 minutes to about 1 hour, preferablyabout 30 minutes.

The compound of formula XXXII is prepared from a compound of formulaXXXIII by reaction with an alkylating reagent of the formula R²L′,wherein L′ is halo or other leaving group such as mesyl, in the presenceof a base and a solvent. Suitable bases include sodium hydride andcesium carbonate. Suitable solvents include dimethyl sulfoxide,NN-dimethylformamide. The aforesaid reaction is conducted at atemperature from about 0° C. to about 30° C., preferably about 22° C.,for a period from about 10 minutes to about 2 hours, preferably about 1hour.

Compounds of the formula XXXIII are commercially available or can bemade by methods well known to those of ordinary skill in the art Scheme8 refers to an alternate preparation of compounds of the formula XXVI,wherein R² is optionally substituted (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,and (C₁-C₁₀)heterocyclic; which are intermediates in Scheme 6 useful inthe preparation of compounds of formula I, wherein R² is optionallysubstituted (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, and (C₁-C₁₀)heterocyclic.Referring to Scheme 8, a compound of formula XXVI is prepared from acompound of formula XXVIII by reaction with sodium nitrite under acidicconditions. Suitable acids include hydrochloric acid. The aforesaidreaction is conducted at a temperature from about 0° C. to about 100°C., preferably about 22° C., for a period from about 1 hour to about 3hours, preferably about 2 hours.

The compound of formula XXVIII, wherein R² is optionally substituted(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, or (C₁-C₁₀)heterocyclic; is preparedfrom a compound of formula XXXI by reductive alkylation with a compoundof the formula R¹(C═O)R¹, wherein each R¹ is independently selected. Oneof ordinary skill in the art will understand that R¹(C═O)R¹ is theprecursor to R² which is formed by reduction in the presence of areducing agent and a solvent. Suitable reducing agents include sodiumborohydride, sodium cyanoborohydride and sodium triacetoxyborohydride,preferably triacetoxyborohydride. Suitable solvents include acetic acid,THF, DMF and dimethylsulfoxide, preferably a mixture of acetic acid, THFand DMF. The aforesaid reaction is conducted at a temperature from about0° C. to about 30° C., preferably about 22° C., for a period from about10 minutes to about 2 hours, preferably about 1 hour.

The compound of formula XXXI is commercially available or can be made bymethods well known to those of ordinary skill in the art.

The compounds of the formula I which are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent, and subsequently convert the free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as chloride, bromide, iodide,nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate,lactate, citrate or acid citrate, tartrate or bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate andpamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of the formula I which are also acidic in nature, e.g.,where R², R³, R⁴, R⁵, R⁶, or R⁷ includes a COOH or tetrazole moiety, arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the herein described acidic compounds offormula 1. These non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium, calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum product yields.

The activity of the compounds of the invention for the various disordersdescribed above can be determined according to one or more of thefollowing assays. All of the compounds of the invention, that weretested, had an IC₅₀ of less than 10 μM in the TNFα and MAPKAP in vitroassays or an ED50 of less than 50 mg/kg in the in vivo TNFα assay.

The compounds of the present invention also possess differentialactivity (i.e. are selective for) for one or more p38 kinases (i.e. α,β, χ and δ). Certain compounds are selective for p38α over p38β, χ andδ, other compounds are selective for p38β over p38α, χ and δ, othercompounds are selective for p38 α and β over p38 χ and δ. Selectivity ismeasured in standard assays as an IC₅₀ ratio of inhibition in eachassay.

Inhibition of TNF-Alpha Production by Human LPS—Treated Monocytes

Mononuclear cells are isolated from heparinized blood (1.5 ml of 1000units/ml heparin for injection, Elkins-Sinn, Inc. added to each 50 mlsample) using Accuspin System-Histopaque-1077 tubes® (Sigma A-7054).Thirty-five milliliters of whole blood are added to each tube and thetubes are centrifuged at 2100 rpm for 20 minutes in a Beckman GS-6KRcentrifuge with the brake off at room temperature. The mononuclear cellswhich collect at the interface are removed, diluted with Macrophageserum free medium (Gibco-BRL) (Medium) to achieve a final volume of 50ml, and collected by centrifugation for 10 minutes. The supernatant isdiscarded and the cell pellet is washed 2 times with 50 ml of Medium. Asample of the suspended cells is taken before the second wash forcounting. Based on this count, the washed cells are diluted with Mediumcontaining 1% FBS to a final concentration of 2.7×10⁶ cells 1 ml and 75μl of the cell suspension is added to each well of a 96 well plate.

Compound Preparation:

Compounds are routinely tested at final concentrations from 2 μM to0.016 μM, but may be tested at other concentrations, depending onactivity. Test agents are diluted with DMSO to a final concentration of2 mM. From this stock solution, compounds are first diluted 1:25 (5 μlof 2 mM stock+120 μl Medium containing 400 ng/ml LPS and 1% FBS then 40μl of this dilution is diluted with 360 μl of Medium with LPS. Serialdilutions (1/5) are performed by transferring 20 μl of this dilution to80 μl of Medium containing both LPS and 0.4% DMSO, resulting insolutions containing 8 μM, 1.6 μM, 0.32 μM and 0.064 μM of test agent.

Assay:

The assay is initiated by adding 25 μl of the diluted compounds to themononuclear cell suspension and incubating the cells at 37 C and 5% CO₂for 4 hours.

The 96-well plates are then centrifuged for 10 minutes at 2000 rpm at 4°C. in a Beckman GS-6KR centrifuge to remove cells and cell debris. A 90pi aliquot of each supernatant is removed and transferred to a 96 wellround bottom plate, and this plate is centrifuged a second time toinsure that all cell debris is removed. 80 ill of the supernatant isremoved and transferred to a new round bottom plate.

Supernatants are analyzed for TNF-α content using R&D ELISA. 25 μl ofeach sample is added to an ELISA well containing 25 μl of assay diluentRD1F and 75 μl of assay diluent RD5. The assay is run following kitdirections except 100 μl of conjugate and substrate solutions are used.

Interpretation

The amount of TNF-α immunoreactivity in the samples is calculated asfollows:

% Control=(X−B)/(TOT−B)X100

where X=OD₄₅₀ nm of the test compound well

B=OD₄₅₀ of Reagent Blank wells on the ELISA

Total=OD₄₅₀ of cells that were treated with 0.1% DMSO only.

MAPKAP Kinase-2 Assay

Monocyte Preparation.

Mononuclear cells are collected from heparinized human blood as detailedabove. The washed cells are seeded into 6-well cluster plates at adensity of 1×10⁷ cells/well (in 2 ml of Medium). The plates areincubated at 37° C. in a 5% CO₂ environment for 2 hours to allowadherence of the monocytes, after which time media supernatantscontaining non-adherent cells are removed by aspiration and 2 ml offresh medium are added to each well. Plates are incubated overnight at37° C. in a 5% CO₂ environment.

Cell Activation:

Media are removed by aspiration. The attached cells are rinsed twicewith fresh Medium, then 2 ml of D-MEM medium containing 10% heatinactivated FBS are added to each well. Test compounds are prepared as30 mM stock solutions in DMSO and diluted to 1250, 250, 50, 10, 2, and0.4 μM in D-MEM containing 1% DMSO and 10% FBS. To individual wells ofthe monocyte cultures, 20 μl of these test agent dilutions are addedresulting in final test agent concentrations of 12.5, 2.5, 0.5, 0.1,0.02 and 0.004 μM. After a 10 minute preincubation period, 20 μl of a 10μg/ml LPS solution are added to each well and the plates are incubatedat 37° C. for 30 min. Media subsequently are removed by aspiration, theattached monocytes are rinsed twice with phosphate buffered saline, then1 ml of phosphate buffered saline containing 1% Triton X-100 (LysisBuffer; also containing 1 Complete™ tablet [Boehringer #1697498] per 10ml of buffer) is added to each well. The plates are incubated on ice for10 minutes, after which the lysates are harvested and transferred tocentrifugation tubes. After all samples are harvested, they areclarified by centrifugation (45,000 rpm for 20 min) and the supernatantsrecovered.

MAPKAP Kinase-2 Immunoprecipitation:

5 III of anti-MAPKAP kinase-2 antiserum (Upstate Biotechnology #06-534)is added to a microcentrifuge tube (1 tube for each of the above celllysates) containing 1 ml of a 5% suspension of Protein G-Sepharose(Sigma #P3296) in PBS. These mixtures are incubated for 1 hour at 4° C.(with rocking) after which the beads, containing bound IgG, arerecovered by centrifugation and washed twice with 1 ml of 50 mM Tris, pH7.5, 1 mM EDTA, 1 mM EGTA, 0.5 mM orthovanadate, 0.1% 2-mercaptoethanol,1% Triton X-100, 5 mM sodium pyrophosphate, 10 mM sodiumβ-glycerophosphate, 0.1 mM phenylmethylsulfonyl fluoride, 1 μg/mlleupeptin, 1 μg/ml pepstatin, and 50 mM sodium fluoride (Buffer A) byrepeated centrifugation. An individual monocyte cell extract (preparedabove) is then transferred to each tube containing a pellet ofIgG-coated Protein G-Sepharose, and these mixtures are incubated for 2hours at 4° C. (with rocking). The beads subsequently are harvested bycentrifugation, and the resulting bead pellets are washed once with 0.5ml of Buffer A containing 0.5 M NaCl, once with 0.5 ml of Buffer A, andonce with 0.1 ml of a buffer composed of 20 mM MOPS, pH 7.2, 25 mMsodium β-glycerophosphate 5 mM EGTA, 1 mM orthovanadate, and 1 mMdithiothreitol (Buffer B).

MAPKAP Kinase-2 Activity Assessment.

A kinase reaction mixture stock is prepared as follows: 2.2 μl of 10mCi/ml γ[³²P]ATP, 88 μl of 1.3 μg/ml solution of MAPKAP Kinase-2substrate peptide (Upstate Biotechnology #12-240), 11 μl of 10 mM ATP,8.8 μl of 1 M MgCl₂, and 770 μl of Buffer B. To each of the immunecomplex-Protein G-pellets, 40 μl of the kinase reaction mixture areadded and the tubes are incubated for 30 minutes at 30° C. The tubesthen are clarified by centrifugation and 25 μl of each supernatant isspotted onto a P81 filter paper disk (Whatman #3698-023). After allowingall fluid to soak into the filter, each disk is placed into anindividual well of 6-well cluster plates and the filters are washedsequentially with 2 ml of 0.75% phosphoric acid (3 washes/15 min each)and once with acetone (10 min). The filters then are air dried andtransferred to liquid scintillation vials containing 5 ml ofscintillation fluid. Radioactivity is determined in a liquidscintillation counter. The amount of radioactivity bound to the filterat each test agent concentration is expressed as a percentage of thatobserved from cells stimulated with LPS in the absence of a test agent.

In vivo Inhibition of TNFα

Rats were weighed and dosed with vehicle (0.5% methyl cellulose, Sigma)or drug. One hour later, animals were injected i.p. with LPS (50 ug/rat,Sigma L-4130). Ninety minutes later, animals were sacrificed byasphyxiation with CO₂ and bled by cardiac puncture. Blood was collectedin Vaccutainer tubes and spun for 20 minutes at 3000 rpm. Serum wasassayed for TNFα levels using an ELISA (R&D Systems).

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous), topical or rectal administration or in aform suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of formula I can also be formulated for sustained deliveryaccording to methods well known to those of ordinary skill in the art.Examples of such formulations can be found in U.S. Pat. Nos. 3,538,214,4,060,598, 4,173,626, 3,119,742, and 3,492,397, which are hereinincorporated by reference in their entirety.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (inflammation) is 0.1 to200 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to abovein the average adult human are preferably arranged so that each metereddose or “puff” of aerosol contains 20 μg to 1000 μg of the compound ofthe invention. The overall daily dose with an aerosol will be within therange 100 μg to 10 mg. Administration may be several times daily, forexample 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses eachtime.

Aerosol combination formulations for treatment of the conditionsreferred to above (e.g., adult respiratory distress syndrome) in theaverage adult human are preferably arranged so that each metered dose or“puff” of aerosol contains from about 1 μg to 1000 μg of the compound ofthe invention. The overall daily dose with an aerosol will be within therange 100 μg to 10 mg. Administration may be several times daily, forexample 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses eachtime.

Aerosol formulations for treatment of the conditions referred to above(e.g., adult respiratory distress syndrome) in the average adult humanare preferably arranged so that each metered dose or “puff” of aerosolcontains from about 20 μg to 1000 μg of the compound of the invention.The overall daily dose with an aerosol will be within the range 100 μgto 10 mg of the p38 kinase inhibitor. Administration may be severaltimes daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or3 doses each time.

This invention also encompasses pharmaceutical compositions containingand methods of treating or preventing comprising administering prodrugsof compounds of the formula 1. Compounds of formula I having free amino,amido, hydroxy or carboxylic groups can be converted into prodrugs.Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues which are covalently joined through peptide bonds to freeamino, hydroxy or carboxylic acid groups of compounds of formula 1. Theamino acid residues include the 20 naturally occurring amino acidscommonly designated by three letter symbols and also include,4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amidesand alkyl esters which are covalently bonded to the above substituentsof formula I through the carbonyl carbon prodrug sidechain.

The following Examples illustrate the preparation of the compounds ofthe present invention. Melting points are uncorrected. NMR data arereported in parts per million (d) and are referenced to the deuteriumlock signal from the sample solvent (deuteriochloroform unless otherwisespecified). Mass Spectral data were obtained using a Micromass ZMD APCIMass Spectrometer equipped with a Gilson gradient high performanceliquid chromatograph. The following solvents and gradients were used forthe analysis. Solvent A; 98% water/2% acetonirile/0.01% formic acid andsolvent B; acetonitrile containing 0.005% formic acid. Typically, agradient was run over a period of about 4 minutes starting at 95%solvent A and ending with 100% solvent B. The mass spectrum of the majoreluting component was then obtained in positive or negative ion modescanning a molecular weight range from 165 AMU to 1100 AMU. Specificrotations were measured at room temperature using the sodium D line (589nm). Commercial reagents were utilized without further purification. THFrefers to tetrahydrofuran. DMF refers to N,N-dimethylformamide.Chromatography refers to column chromatography performed using 32-63 mmsilica gel and executed under nitrogen pressure (flash chromatography)conditions. Room or ambient temperature refers to 20-25° C. Allnon-aqueous reactions were run under a nitrogen atmosphere forconvenience and to maximize yields. Concentration at reduced pressuremeans that a rotary evaporator was used.

One of ordinary skill in the art will appreciate that in some casesprotecting groups may be required during preparation. After the targetmolecule is made, the protecting group can be removed by methods wellknown to those of ordinary skill in the art, such as described in Greeneand Wuts, “Protective Groups in Organic Synthesis” (2^(nd) Ed, JohnWiley & Sons 1991).

EXAMPLE 1

6-[5-(4-FLUORO-3-METHYL-PHENYL)-3H-IMIDAZOL-4-YL]-1-ISOPROPYL-1H-BENZOTRIAZOLE

To a stirred solution of 3-isopropyl-3H-benzotriazole-5-carbaldehyde(150 mg) in 15 mL of THF was added 0.16 mL of concentrated ammoniumhydroxide. The flask was sealed with a plastic cap and stirredovernight. Piperazine (75 mg) was added, followed by4-fluoro-3-methylphenyl-toylsulfonomethylisocyanide (312 mg), and themixture was stirred overnight. The mixture was filtered and the filtratewas concentrated and purified by flash chromatography (eluting with 4:1ethyl acetate/hexanes to give 130 mg of the title compound. MASSSPECTRUM 336 M+1.

EXAMPLE 2

6-[4-(4-FLUORO-PHENYL)-OXAZOL-5-YL]-1-ISOPROPYL-H-BENZOTRIAZOLE

A solution of 3-isopropyl-3H-benzotriazole-5-carbaldehyde (60 mg),potassium carbonate (49 mg), and4-fluorophenyl-toylsulfonomethylisocyanide (101 mg) in 7.5 mL ofdimethyl formamide was stirred overnight. The reaction mixture wasconcentrated to 1 mL of volume and heated at 75° C. for 2 hours. Themixture was cooled to 22° C., diluted with water, and extracted withethyl acetate. The extract was washed with water, dried (sodiumsulfate), filtered, and the filtrate was concentrated. The residue waspurified by flash chromatography (eluting with 2:3 ethylacetate/hexanes) to give 80 mg of6-[4-(4-fluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole; MASSSPECTRUM 323 (M+1).

The following compounds were made in an analogous fashion to the methodsdescribed in Examples 1 or 2.

EXAMPLE 3

6-[5-(4-FLUORO-PHENYL)-3H-IMIDAZOL-4-YL]-1-ISOPROPYL-1H-BENZOTRIAZOLE

MASS SPECTRUM 322 (M+1).

EXAMPLE 4

6-[4-(4-FLUORO-3-METHYL-PHENYL)-OXAZOL-5-YL]-1-ISOPROPYL-1H-BENZOTRIAZOLE

MASS SPECTRUM 337 (M+1).

EXAMPLE 5

6-[5-(4-FLUORO-PHENYL)-3H-IMIDAZOL-4-YL]-1-METHYL-1H-BENZOTRIAZOLE

MASS SPECTRUM 294 (M+1).

EXAMPLE 6

1-METHYL-6-(5-M-TOLYL-3H-IMIDAZOL-4-YL)-1H-BENZOTRIAZOLE

MASS SPECTRUM 290 (M+1).

EXAMPLE 7

1-METHYL-6-(5-PHENYL-3H-IMIDAZOL-4-YL)-1H-BENZOTRIAZOLE

MASS SPECTRUM 276 (M+1).

EXAMPLE 8

6-[4-(4-FLUORO-PHENYL)-OXAZOL-5-YL]-1-ISOPROPYL-1H-BENZOTRIAZOLE

MASS SPECTRUM 323 (M+1).

EXAMPLE 9

1-ISOPROPYL-6-(5-PHENYL-3H-IMIDAZOL-4-YL)-1H-BENZOTRIAZOLE

MASS SPECTRUM 304 (M+1).

EXAMPLE 10

1-ISOPROPYL-6-(4-PHENYL-OXAZOL-5-YL)-1H-BENZOTRIAZOLE

MASS SPECTRUM 305 (M+1).

EXAMPLE 11

6-[5-(4-FLUORO-3-METHYL-PHENYL)-3H-IMIDAZOL-4-YL]-1-METHYL-1H-BENZOTRIAZOLE

MASS SPECTRUM 308 (M+I).

EXAMPLE 12

1-ETHYL-6-(4-M-TOLYL-OXAZOL-5-YL)-1H-BENZOTRIAZOLE

MASS SPECTRUM 304(M+1).

EXAMPLE 13

1-ETHYL-6-(5M-TOLYL-3H-IMIDAZOL-4-YL)-1H-BENZOTRIAZOLE

MASS SPECTRUM 304 (M+1).

EXAMPLE 14

1-ETHYL-6-[4-(4-FLUORO-PHENYL)-OXAZOL-5yl]-1H-BENZOTRIAZOLE

MASS SPECTRUM 309 (M+1).

EXAMPLE 15

1-ETHYL-6-[5-(4-FLUORO-PHENYL)-3H-IMIDAZOL-4-YL]-1H-BENZOTRIAZOLE

MASS SPECTRUM 308 (M+1).

EXAMPLE 16

6-[3-BENZYL-5-(4-FLUORO-3-METHYL-PHENYL)-3H-IMIDAZOL-4-YL]-1-ISOPROPYL-1H-BENZOTRIAZOLE

MASS SPECTRUM 426 (M+1).

EXAMPLE 17

6-[5-(4-FLUORO-PHENYL)-3S-PYRROLIDIN-3-YL-3H-IMIDAZOL-4-YL]-1-ISOPROPYL-1H-BENZOTRIAZOLEMONO CITRATE SALT

MASS SPECTRUM 391 (M+1).

EXAMPLE 18

6-[5-(4-FLUORO-PHENYL)-3R-PYRROLIDIN-3-YL-3H-IMIDAZOL-4-YL]-1-ISOPROPYL-1H-BENZOTRIAZOLE

MASS SPECTRUM 391 (M+1).

EXAMPLE 19

6-[5-(4-FLUORO-PHENYL)-2-PYRIDIN-3-YL-3H-IMIDAZOL-4-YL]-1-ISOPROPYL-1H-BENZOTRIAZOLE

Step (A)2-(4-Fluoro-phenyl)-1-(3-isopropyl-3H-benzotriazol-5-yl)-ethanone

To a stirred, cold (−10° C.) mixture of 519 mg3-isopropyl-3H-benzotriazole-5-carboxylic acid methoxy-methyl-amide in 2mL of tetrahydrofuran was added 17 mL of 4-fluorophenylmagnesium bromide(0.25 M in diethyl ether). The resulting suspension was stirred for 1hour before the mixture was concentrated to near dryness. The residuewas taken-up into 20 mL of tetrahydrofuran and 6 mL more4-fluorophenylmagnesium bromide (0.25 M in diethyl ether) was added. Theresulting solution was stirred for 15 minutes before it was diluted withwater and the pH of the mixture was adjusted to 7 using 1 M hydrochloricacid. The mixture was extracted with ethyl acetate (3×), and thecombined extracts were washed with brine, dried (sodium sulfate),filtered, and the filtrate was concentrated to give about 1 g of ayellow oil. This oil was purified by flash chromatography (eluting with3:1 hexanes/ethyl acetate) to give 467 mg of2-(4-fluoro-phenyl)-1-(3-isopropyl-3H-benzotriazol-5-yl)-ethanone as aclear oil.

Step (B)2-Bromo-2-(4-fluoro-phenyl)-1-(3-isopropyl-3H-benzotriazol-5-yl)-ethanone

To a stirred solution of 191 mg of2-(4-fluoro-phenyl)-1-(3-isopropyl-3H-benzotriazol-5-yl)-ethanone in 2mL of acetic acid was added 0.64 mL of bromine (1 M in acetic acid). Themixture was heated at 50° C. for 3 hours. The reaction mixture wascooled to 22° C. and concentrated to dryness. The residue was taken-upinto ethyl acetate and washed with saturated aqueous sodium bicarbonate,brine; the organic layer was dried (sodium sulfate), filtered and thefiltrate was concentrated to give 222 mg of2-bromo-2-(4-fluoro-phenyl)-1-(3-isopropyl-3H-benzotriazol-5-yl)-ethanoneas a light yellow oil. This material was used without furtherpurification.

Step (C)6-[5-(4-Fluoro-phenyl)-2-pyridin-3-yl-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole

To a stirred solution of 29 mg of2-bromo-2-(4-fluoro-phenyl)-1-(3-isopropyl-3H-benzotriazol-5-yl)-ethanonein 0.38 mL of N,N-dimethylformamide was added 75 mg of cesium carbonateand 24 mg of 3-amidinopyridine hydrochloride. The mixture was heated at50° C. for 30 min. The orange-brown mixture was cooled to 22° C.,transferred to a separatory funnel with water, and extracted with ethylacetate (3×). The combined organic layers were washed with brine, dried(sodium sulfate), filtered, and the filtrate was concentrated to anorange oil. This oil was purified by flash chromatography (eluting withethyl acetate) to give 12 mg of6-[5-(4-fluoro-phenyl)-2-pyridin-3-yl-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazoleas a white solid. LCMS m/z 399 (M+1).

The following Examples were prepared according to the methods analogousto those of Example 19.

EXAMPLE 20

1-METHYL-6-(2-PYRAZIN-2-YL-5-M-TOLYL-3H-IMIDAZOL-4-YL)-1H-BENZOTRIAZOLE

MASS SPECTRUM 368 (M+1).

EXAMPLE 21

N-[5-(3-METHYL-3H-BENZOTRIAZOL-5-YL)-4-M-TOLYL-1H-IMIDAZOL-2-YL]-ACETAMIDE

MASS SPECTRUM 347 (M+1).

EXAMPLE 22

1-METHYL-6-(2-PYRIDIN-3-YL-5-M-TOLYL-3H-IMIDAZOL-4-YL)-1H-BENZOTRIAZOLE

MASS SPECTRUM 367(M+1).

EXAMPLE 23

1-ISOPROPYL-6-(2-PYRIDIN-3-YL-5-M-TOLYL-3H-IMIDAZOL-4-YL)-1H-BENZOTRIAZOLE

MASS SPECTRUM 395 (M+1).

EXAMPLE 24

6-[5-(4-FLUORO-PHENYL)-2-PYRAZIN--2-YL-3H-IMIDAZOL-4-YL]-1-ISOPROPYL-1H-BENZOTRIAZOLE

MASS SPECTRUM 400 (M+1).

Preparation 1

1-METHYL-1H-BENZOTRIAZOLE-5-CARBALDEHYDE

3-Methyl-3H-benzotriazole-5-carboxylic Acid Methyl Ester

To a stirred, cold (0° C.) solution of 1,2,3-benzotriazole-5-carboxylicacid methyl ester (2.51 g) in dimethylformamide was added 60% sodiumhydride (370 mg) portion wise. After 20 minutes, methyl iodide (0.87 mL)was added. The reaction was quenched by the addition of water after 30minutes. The mixture was extracted with ethyl acetate; the extracts werewashed with water, and brine, and dried (sodium sulfate). Filtration andconcentration of the filtrate gave a residue from which 716 mg of1-methyl-1H-benzotriazole-5-carboxylic acid methyl ester crystallized(hot ethyl acetate). The mother liquor was purified by flashchromatography (eluting with 3:2 hexanes/ethyl acetate) to give 890 mgof 2-methyl-2H-benzotriazole-5-carboxylic acid methyl ester and 490 mgof 3-methyl-3H-benzotriazole-5-carboxylic acid methyl ester. Structuralassignments were made on the basis of proton NMR and nOe experiments.

1-Methyl-1H-benzotriazole-5-carbaldehyde

3-Methyl-3H-benzotriazole-5-carboxylic acid methyl ester was taken onseparately to the corresponding aldehydes by reduction with lithiumaluminum hydride (1 equivalent) in anhydrous dimethoxyethane. Theresulting alcohols were oxidized using2,2,6,6-tetramethyl-1-piperidinyloxy free radical (1 equivalent),tetrabutylammonium chloride (1 equivalent), and N-chlorosuccinimide (1.3equivalent) in methylene chloride and pH 8.6 sodiumbicarbonate/potassium carbonate buffer to give3-methyl-3H-benzotriazole-5-carbaldehyde.

Preparation 2

3-ISOPROPYL-3H-BENZOTRIAZOLE-5-CARBALDEHYDE

3-Isopropyl-3H-benzotriazole-5-carboxylic Acid

To a stirred mixture of 3,4-diaminobenzoic acid (15.2 g), in 200 mL oftetrahydrofuran, 30 mL of dimethyl formamide, 7.3 mL of acetone, and 5.7mL of acetic acid, was added 31.8 9 of sodium triacetoxyborohydride inportions. After 3 hours the mixture was filtered through diatomaceousearth and washed with tetrahydrofuran. The filtrate was concentrated todryness. Crystallization of the residue with ethyl acetate/hexanes gave11 grams of 4-amino-3-isopropylamino-benzoic acid.

To a stirred, cold (0° C.) mixture of 4-amino-3-isopropylamino-benzoicacid (11 g) in 120 mL of 6 N hydrochloric acid was added drop-wise asolution of 5.9 g of sodium nitrite in 40 mL of water. After 2 hours thesolids were collected by filtration, washed with water, and dried togive 9 grams of 3-isopropyl-3H-benzotriazole-5-carboxylic acid.

3-isopropyl-3H-benzotriazole-5-carboxylic Acid methoxy-methyl-amide

To a stirred mixture of 3-isopropyl-3H-benzotriazole-5-carboxylic acid(9 g) in 150 mL of methylene chloride and 0.15 mL of DMF was added 5.0mL of oxalyl chloride. The solution was stirred overnight before 27 mLof N,N-diisopropylamine and 5.6 g of N,O-dimethylhydroxylaminehydrochloride was added. The mixture was stirred for 3 days beforemixture was washed with a solution of sodium dihydrogenphosphate,aqueous bicarbonate, dilute hydrochloric acid, brine, dried (sodiumsulfate), filtered, and the filtrate was concentrated to a dark oil.This oil was purified by flash chromatography (eluting with 3:2 ethylacetate/hexanes) to afford 10.4 g of3-isopropyl-3H-benzotriazole-5-carboxylic acid methoxy-methyl-amide asbrown oil.

3-isopropyl-3H-benzotriazole-5-carbaldehyde

To a stirred, cold (−78° C.) solution of3-isopropyl-3H-benzotriazole-5-carboxylic acid methoxy-methyl-amide(4.26 g) in 20 mL of toluene was added drop-wise 17.2 mL of DIBAL intoluene (1 M). The mixture was stirred for 1 hour at −78° C. beforewarming to 0° C. The reaction was quenched with aqueous 1 N hydrochloricacid, diluted with water and extracted with ethyl acetate (3 times). Thecombined extracts were washed with water, brine, dried (sodium sulfate),filtered, and the filtrate was concentrated to give a yellow oil. Thisoil was purified by flash chromatography (eluting with 2:1 hexanes/ethylacetate) to give 2.24 g of 3-isopropyl-3H-benzotriazole-5-carbaldehydeas a yellow oil which crystallized upon standing; MS 190 M+1.

Preparation 3

3-ETHYL-3H-BENZOTRIAZOLE-5-CARBALDEHYDE

3-Chloro-4-nitro-benzonitrile

Sodium nitrite (6.78 g in water (40 mL) at 0° C.) was slowly added to asolution of 4-amino-3-chloro-benzonitrile (10.5 g) in water (30 mL) andconcentrated hydrochloric acid (30 mL) also at 0° C. After 10 minutesthe solution was poured onto a suspension of cuprous oxide (3.48 g) andsodium nitrite (31.69 g) in water (100 mL) at 0° C. The ensuing mixturewas stirred at 0° C. for 1 hour then at 23° C. for 1 hour. The resultingmixture was extracted with dichloromethane and the organic layer washedwith saturated sodium chloride. The separated organic layer was driedover sodium sulfate and then concentrated to give3-chloro-4-nitro-benzonitrile (11.31 g).

3-Ethylamino-4-nitro-benzonitrile

Monoethylamine was bubbled though a solution of3-chloro-4-nitro-benzonitrile (0.49 g) in tetrahydrofuran (1 mL). Thereaction vial was sealed and allowed to stand for 18 hours at 23° C. Theresulting mixture was diluted with ethyl acetate and saturated sodiumbicarbonate and extracted. The organic layer was dried with sodiumsulfate and concentrated. Silica gel chromatography using 5% ethylacetate in hexanes as eluent gave 3-ethylamino-4-nitro-benzonitrile (0.3g).

4-Amino-3-ethylamino-benzonitrile

3-Ethylamino-4-nitro-benzonitrile (0.3 g) was diluted with ethanol (5mL) and was treated with 10% palladium on carbon (Pd/C)(0.070 g). Themixture was then shaken in a hydrogenation shaker under an atmosphere ofhydrogen (40 psi) for 30 minutes. The resulting mixture was filteredthrough diatomaceous earth and concentrated. Silica gel chromatographyusing 20% ethyl acetate in hexanes as eluent gave4-amino-3-ethylamino-benzonitrile (0.08 g).

3-Ethyl-3H-benzotriazole-5-carbonitrile

3-Ethyl-3H-benzotriazole-5-carbonitrile was prepared using theprocedures previously described for the synthesis of3-isopropyl-3H-benzotriazole-5-carboxylic acid ethyl ester.

3-Ethyl-3H-benzotriazole-5-carboxylic Acid

3-Ethyl-3H-benzotriazole-5-carbonitrile (0.065 g) was diluted withlithium hydroxide (2 M in water) then heated to 100° C. for 2 hours. Themixture was then cooled to 23 C, acidified with 1 N hydrochloric acidand extracted with ethyl acetate. The organic layer was dried withsodium sulfate and concentrated to give3-ethyl-3H-benzotriazole-5-carboxylic acid (0.059 g).

3-Ethyl-3H-benzotriazole-5-carboxylic Acid Methyl Ester

3-Ethyl-3H-benzotriazole-5-carboxylic acid (0.15 g) was diluted withmethanol and treated with HCl (gas). The reaction was then heated to 65°C. for 18 hours. The mixture was allowed to cool to 23° C. and wasdiluted with saturated sodium bicarbonate and extracted with ethylacetate. The organic layer was dried with sodium sulfate andconcentrated to give 3-ethyl-3H-benzotriazole-5-carboxylic acid methylester (0.143 g).

(3-Ethyl-3H-benzotriazol-5-yl)-methanol

3-Ethyl-3H-benzotriazole-5-carboxylic acid methyl ester (0.143 g) wasdiluted with tetrahydrofuran (2 mL) and methanol (0.06 mL). Lithiumborohydride (0.023 g) was added and the solution was allowed to stand at23° C. for 30 minutes. The reaction was then poured onto saturatedammonium chloride and extracted with ethyl acetate. The organic layerwas dried with sodium sulfate and concentrated to give(3-Ethyl-3H-benzotriazol-5-yl)-methanol (0.13 g).

3-Ethyl-3H-benzotriazole-5-carbaldehyde

3-Ethyl-3H-benzotriazole-5-carbaldehyde was prepared from(3-Ethyl-3H-benzotriazol-5-yl)-methanol by a Swern oxidation.

What is claimed is:
 1. A compound of the formula

wherein Het is an optionally substituted 5-membered heteroaryl whichtaken together with (R³—)_(s) phenyl is selected from the groupconsisting of

R² is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, phenyl, (C₁-C₁₀)heteroaryl and (C₁-C₁₀)heterocyclic;wherein each of the aforesaid (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, phenyl,(C₁-C₁₀)heteroaryl and (C₁-C₁₀)heterocyclic substituents may optionallybe independently substituted by one to four moieties independentlyselected from the group consisting of halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, phenyl,(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, formyl,—CN, (C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,phenyl-NH—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, H₂N—(C═O)—NH—,(C₁-C₆)alkyl-HN—(C═O)—NH—, [(C₁-C₆)alkyl-]₂N—(C═O)—NH—,(C₁-C₆)alkyl-HN—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₁-C₆)alkyl-]₂N—(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-HN—(C═O)—NH—,(phenyl-)₂N—(C═O)—NH—, phenyl-HN—(C═O)—[((C₁-C₆)alkyl)—N]—,(phenyl-)₂N—(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₆)alkyl-O—(C═O)—NH—,(C₁-C₆)alkyl-O—(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-O—(C═O)—NH—,phenyl-O—(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₆)alkyl-SO₂NH—, phenyl-SO₂NH—,(C₁-C₆)alkyl-SO₂—, phenyl-SO₂—, hydroxy, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, phenoxy, (C₁-C₆)alkyl-(C═O)—O—, phenyl-(C═O)—O—,H₂N—(C═O)—O—, (C₁-C₆)alkyl-HN—(C═O)—O—, [(C₁-C₆)alkyl-]₂N—(C═O)—O—,phenyl-HN—(C═O)—O—, and (phenyl-)₂N—(C═O)—O—; wherein two adjacent R²substituents on said (C₃-C₁₀)cycloalkyl, phenyl, (C₁-C₁₀)heteroaryl or(C₁-C₁₀)heterocyclic may be taken together with the carbon or heteroatomto which they are attached to form a five to six membered carbocyclic orheterocyclic ring; wherein each of said moieties containing a phenylalternative may optionally be substituted by one or two radicalsindependently selected from the group consisting of (C₁-C₆)alkyl, halo,(C₁-C₆)alkoxy, (C₁-C₆)alkyl and perhalo(C₁-C₆)alkoxy; each R³ isindependently selected from the group consisting of halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy, (C₁-C₁₀)heteroaryl-O—,(C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C—C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)— and(C₁-C₆)alkyl-(C═O)—O—; wherein two adjacent R³ substituents mayoptionally be taken together to form a three to six membered carbocyclicor heterocyclic ring; s is an integer from zero to five; R⁴ and R⁶ areeach independently selected from the group consisting of hydrogen, haloand R⁹—B—(CH₂)_(n)—; n is an integer from zero to six; each B isindependently a bond, —(CHR¹⁰)—, —O—, —S—, —(SO₂)—, —(C═O)—, —O(C═O)—,—(C═O)—O—, —(C═O)—NR¹⁰—, —(R¹⁰—N)—, —(R¹⁰—N)—SO₂—, —(R¹⁰—N)—(C═O)—,—SO₂—(NR¹¹)—, —(R¹⁰—N)—(C═O)—(NR¹¹)—, —(O)—(C═O)—(NR¹⁰)— or—(R¹⁰—N)—(C═O)—O—; R⁵ and R⁷ are each independently selected from thegroup consisting of hydrogen, R¹⁴—(CR¹⁵H)_(p)—, phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl,(C₁-C₆)alkyl-(SO₂)—, phenyl-(SO₂)—, H₂N—(SO₂)—, (C₁-C₆)alkyl-NH—(SO₂)—,[(C₁-C₆)alkyl-]₂N—(SO₂)—, phenyl-NH—(SO₂)—, (phenyl-)₂N—(SO₂)—,R¹⁶—(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,phenyl-NH—(C═O)—, (C₃-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₆)alkyl-]₂N—(C═O)—, (phenyl-)₂N—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heteroaryl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heterocyclic-[((C₁-C₆)alkyl)—N]—(C═O)—, and(C₃-C₁₀)cycloalkyl-[((C₁-C₆)alkyl)—N]—(C═O)—, wherein each of theaforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R⁵ and R⁷alternatives may optionally be independently substituted by one to fourmoieties independently selected from the group consisting of halo,R¹⁶—(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, phenyl, benzyl, (C₁-C₁₀)heterocyclic,(C₁-C₁₀)heteroaryl, (C₁-C₆)alkyl-SO₂—, formyl, —CN, (C₁-C₆)alkyl-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—, (C₁-C₆)alkyl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—, phenyl-(C═O)—NH—,(C₁-C₁₀)heterocyclic-(C═O)—NH—, (C₁-C₁₀)heteroaryl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—[(C₁-C₆)alkyl-N]—,(C₁-C₆)alkyl-SO₂NH—, (C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—,(C₁-C₁₀)heterocyclic-SO₂NH— and (C₁-C₁₀)heteroaryl-SO₂NH—; wherein eachof said phenyl and heteroaryl moiety alternatives may optionally besubstituted by one or two radicals independently selected from halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, perfluoro(C₁-C₆)alkyl andperfluoro(C₁-C₆)alkoxy; p is an integer from one to six; R⁹ is selectedfrom the group consisting of hydrogen, —CF₃, —C≡N, R¹³—(R¹²CH)_(m)—,phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkyl;wherein each of the aforesaid R⁹ phenyl, (C₁-C₁₀)heteroaryl,(C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkyl substituents may optionallybe substituted by one to four moieties independently selected from thegroup consisting of halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,perhalo(C₁-C₆)alkyl, phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic,(C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,phenoxy, (C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—,(C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-CB)alkyl-O—(C═O)—, H₂N(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—; wherein two adjacent moietieson said R⁹ phenyl, (C₁-C₁₀)heterocyclic or (C₃-C₁₀)cycloalkylsubstituents may be taken together with the carbon or heteroatom towhich they are attached to form a five to six membered heterocyclic orcarbocyclic ring; m is an integer from one to six; R¹⁰ is hydrogen,(C₁-C₆)alkyl-SO₂— or (C₁-C₆)alkyl; R¹¹ is hydrogen or (C₁-C₆)alkyl; eachR¹² is independently selected from the group consisting of hydrogen,amino, (C₁-C₆)alkoxy or (C₁-C₆)alkyl; R¹³ is selected from the groupconsisting of hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl,hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy,(C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—,(C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—,phenyl-SO₂—NH—, (C₁-C₆)alkyl-SO₂—[((C₁-C₆)alkyl)—N]—,phenyl-SO₂—[((C₁-C₆)alkyl)—N]—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—; R¹⁴ is selected from thegroup consisting of hydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, phenyl,(C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl, phenyl-(S═O)—,(C₁-C₆)alkyl-SO₂—, phenyl-SO₂—, H₂N—SO₂—, (C₁-C₆)alkyl-NH—SO₂—,phenyl-NH—SO₂—, [(C₁-C₆)alkyl-]₂N—SO₂—, (phenyl-)₂N—SO₂—, formyl, —CN,(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—,R¹⁶—(C₁-C₆)alkyl-O—(C═O)—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₁₀)heterocyclic-O—(C═O)—, H₂N—(C═O)—, R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heteroaryl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heterocyclic-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₃-C₁₀)cycloalkyl[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy, R¹⁶—(C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—,R¹⁶—(C₁-C₆)alkyl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,R¹⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,phenyl-(C═O)—NH—, (C₁-C₁₀)heterocyclic-(C═O)—NH—,(C₁-C₁₀)heteroaryl-(C═O)—NH—,R¹⁶—(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, R¹⁶—(C₁-C₆)alkyl-SO₂NH—,(C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH—and (C₁-C₁₀)heteroaryl-SO₂NH—; wherein each of the aforesaid phenyl,heterocyclic, heteroaryl or cycloalkyl R¹⁴ alternatives may optionallybe independently substituted by one to four moieties independentlyselected from the group consisting of halo, R¹⁶—(C-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,phenyl, benzyl, (C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl,(C₁-C₆)alkyl-SO₂—, formyl, —CN, R¹⁶—(C₁-C₆)alkyl-(C═)—,(C₃-C₁₀)cycloalkyl-(C═O)—, phenyl-(C═O)—, ((C₁-C₁₀)heterocyclic-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₁₀)heteroaryl-O—(C═O)—, H₂N—(C═O)—, R¹⁶—(C-C₆)alkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy,R¹⁶-(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—,R¹⁶—(C₁-C₆)alkyl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,R¹⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,R¹⁶(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,phenyl-(C═O)—NH—, (C₁-C₁₀)heterocyclic-(C═O)—NH—,(C₁-C₁₀)heteroaryl-(C═O)—NH—, R¹⁶(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, R¹⁶—(C₁-C₆)alkyl-SO₂NH—,(C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH—and (C₁-C₁₀)heteroaryl-SO₂NH—; wherein each of said phenyl andheteroaryl moiety alternatives may optionally be substituted by one ortwo radicals independently selected from the group consisting of halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, perfluoro(C₁-C₆)alkyl andperfluoro(C₁-C₈)alkoxy; each R¹⁵ is independently selected from thegroup consisting of hydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,perhalo(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy,(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—O—, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, formamidyl and (C₁-C₆)alkyl-(C═O)—NH—; each R¹⁶is independently selected from the group consisting of hydrogen, halo,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,(C₁-C₁₀)heterocyclic, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—O—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl and(C₁-C₆)alkyl-(C═O)—NH—; wherein said (C₁-C₁₀)heterocyclic may optionallybe substituted by one to three substituents independently selected fromthe group consisting of halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino,(C₁-C₆)alkylamino and [(C₁-C₆)alkyl]₂-amino; or R⁴ and R⁶ or R⁴ and R⁷or R⁵ and R⁶ may be taken together with the atoms to which they areattached to form an optionally substituted five to ten memberedsaturated, unsaturated or aromatic ring optionally containing two tothree heteroatoms independently selected from NH, N, O, S, SO or SO₂;wherein said ring may be optionally substituted by one to threesubstituents independently selected from the group consisting of oxo,halo, (C₁-C₆)alkyl, phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic,(C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy, phenoxy,(C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—,(C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—, phenyl-S—, phenyl-(S═O)—,phenyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, [(C₁-C₆)alkyl]₂—N—SO₂—,phenyl-NH—SO₂—, (phenyl)₂—N—SO₂—, phenyl-[N(C₁-C₆)alkyl]-SO₂—, formyl,(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—,(C₁-C₈)alkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, H₂N—(C═O)—, (C-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[(C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heteroaryl-[(C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—,(C₁-C₁₀)heterocyclic-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-[((C₁-C₆)alkyl)—N]—(C═O)—, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-SO₂—NH—, phenyl-SO₂—NH—,(C₁-C₆)alkyl-SO₂—[((C₁-C₆)alkyl)—N]—, phenyl-SO₂—[((C₁-C₆)alkyl)—N]—,formamidyl, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₁₀)heteroaryl-(C═O)—NH—,(C₁-C₁₀)heteroaryl-(C═O)—[((C₁-C₆)alkyl)-N]—,(C₁-C₁₀)heterocyclic-(C═O)—NH—,(C₁-C₁₀)heterocyclic-(C═O)—[((C₁-C₆)alkyl)—N]—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, H₂N(C═O)—NH—,(C₁-C₆)alkyl-HN—(C═O)—NH—, (C₁-C₆)alkyl-HN—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₁-C₆)alkyl]₂—N—(C═O)—NH—,[(C₁-C₆)alkyl]₂—N—(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-HN—(C═O)—NH—,phenyl-HN—(C═O)—[((C₁-C₆)alkyl)—N]—, (phenyl)₂—N—(C═O)—NH—,(phenyl)₂—N—(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₁₀)heteroaryl-HN—(C═O)—NH—,(C₁-C₁₀)heteroaryl-HN—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₁-C₁₀)heteroaryl]₂—N—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₁-C₁₀)heteroaryl]₂—N—(C═O)—NH—, (C₁-C₁₀)heterocyclic-HN—(C═O)—NH—,(C₁-C₁₀)heterocyclic-HN—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₁-C₁₀)heterocyclic]₂—N—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₁-C₁₀)heterocyclic]₂—N—(C═O)—NH—, (C₃-C₁₀)cycloalkyl-HN—(C═O)—NH—,(C₃-C₁₀)cycloalkyl-HN—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—[((C₁-C₆)alkyl)—N]—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—O—,phenyl-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₆)alkyl-NH—(C═O)—O—, [(C₁-C₆)alkyl]₂—N—(C═O)—O—,phenyl-NH—(C═O)—O—, (C₁-C₁₀)heteroaryl-NH—(C═O)—O—,(C₁-C₁₀)heterocyclic-NH—(C═O)—O— and (C₃-C₁₀)cycloalkyl-NH—(C═O)—O—; ora pharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein R² is optionally substituted (C₁-C₆)alkyl, phenyl,(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)heteroaryl or (C₁-C₁₀)heterocyclic.
 3. Acompound according to claim 1, wherein R² is (C₁-C₆)alkyl, optionallysubstituted with one to four groups independently selected from halo,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkyl, perhalo(C₁-C₆)alkoxy, —CN, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, HO—(C═O)—,(C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, (C₁-C₆)alkyl-CO₂—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₆)alkyl-NH—(C═O)—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,(C₁-C₆)alkyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₆)alkyl-SO₂NH—,(C₁-C₆)alkyl-SO₂—, optionally substituted phenyl-(C═O)—, optionallysubstituted phenyl-(C═O)—O—, optionally substituted phenoxy, optionallysubstituted phenyl-NH—(C═O)—, optionally substitutedphenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, optionally substitutedphenyl-(C═O)—NH— and optionally substitutedphenyl-(C═O)—[((C₁-C₆)alkyl)—N]—.
 4. A compound according to claim 1,wherein R² is (C₁-C₄)alkyl.
 5. A compound according to claim 1, whereinR² is methyl, ethyl or isopropyl.
 6. A compound according to claim 1,wherein R² is optionally substituted (C₃-C₆)cycloalkyl.
 7. A compoundaccording to claim 1, wherein R² is optionally substituted phenyl.
 8. Acompound according to claim 1, wherein R² is phenyl optionallysubstituted by 1 to 3 substituents independently selected from the groupconsisting of fluoro, chloro, trifluoromethyl, hydroxy, (C₁-C₆)alkoxy,amino, trifluoromethoxy, and (C₁-C₆)alkyl.
 9. A compound according toclaim 1, wherein R² is optionally substituted (C₁-C₁₀)heterocyclic. 10.A compound according to claim 1, wherein R² is optionally substituted(C₁-C₁₀)heteroaryl.
 11. A compound according to claim 1, wherein R² ishydrogen.
 12. A compound according to claim 1, wherein the compound hasthe formula


13. A compound according to claim 1, wherein the compound has theformula


14. A compound according to claim 1, wherein the compound has theformula


15. A compound according to claim 1, wherein the compound has theformula


16. A compound according to claim 1, wherein the compound has theformula


17. .A compound according to claim 1, wherein the compound has theformula


18. A compound according to claim 1, wherein the compound has theformula


19. A compound according to claim 1, wherein the compound has theformula


20. A compound according to claim 1, wherein R⁴ is hydrogen.
 21. Acompound according to claim 1, wherein R⁴ is R⁹—B—(CH₂)_(n)— and n iszero.
 22. A compound according to claim 1, wherein R⁴ is R⁹—B—(CH₂)_(n)—and n is an integer from one to five.
 23. A compound according to claim1, wherein R⁴ is R⁹—B—(CH₂)_(n)—; n is zero; B is a bond and R⁹ isR¹³(R¹²CH)_(m)—.
 24. A compound according to claim 1, wherein R⁴ isR⁹—B—(CH₂)_(n)—; n is zero; B is —(C═O)—(R¹⁰—N)—, —(R¹⁰—N)—,—SO₂—(R¹⁰—N)—, —(R¹⁰—N)—(C═O)—(NR¹¹)— or —(R¹⁰—N)—(C═O)—O—; and R⁹ isselected from the group consisting of hydrogen and R¹³—(R¹²CH)_(m)—. 25.A compound according to claim 1, wherein R⁴ is R⁹—B—(CH₂)_(n)—; n iszero; B is —(C═O)—(R¹⁰—N)—, —(R¹⁰—N)—, —SO₂—(R¹⁰—N)—,—(R¹⁰—N)—(C═O)—(NR¹¹)— or —(R¹⁰—N)—(C═O)—O—; R⁹ is R¹³—(R¹²CH)_(m)—; mis 1-6; R¹⁰ is hydrogen or methyl; each R¹² is independently selectedfrom the groups consisting of hydrogen or methyl; and R¹³ is selectedfrom the group consisting of hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl,hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, phenoxy,(C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—,(C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—NH—, phenyl-(C═O)-[((C₁-C₆)alkyl)—N]—,(C₁-C₆)alkyl-SO₂—NH—, phenyl-SO₂—NH—,(C₁-C₆)alkyl-SO₂—[((C₁-C₆)alkyl)—N]—, phenyl-SO₂—[((C₁-C₆)alkyl)—N]—,—CN, (C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₁₀)heteroaryl-NH—(C═O)—, (C₁-C₁₀)heterocyclic-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,H₂N(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,phenyl-NH—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₆)alkyl-(C═O)—O— and phenyl-(C═O)—O—.
 26. A compound according toclaim 1, wherein R⁴ is R⁹—B—(CH₂)_(n)—; n is zero; B is —(R¹⁰—N)—; R⁹ ishydrogen or R¹³—(R¹²CH)_(m)—; m is 1-6; R¹⁰ is hydrogen or methyl; R¹²is hydrogen or methyl; and R¹³ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkyl.27. A compound according to claim 1, wherein R⁷ is selected from thegroup consisting of hydrogen, phenyl, (C₁-C₁₀)heteroaryl,(C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, R⁶—(C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)— and (C₃-C₁₀)cycloalkyl-NH—(C═O)—; whereineach of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R⁷alternatives may optionally be independently substituted by one to fourmoieties independently selected from the group consisting of halo,R¹⁶(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, phenyl, benzyl, (C₁-C₁₀)heterocyclic,(C₁-C₁₀)heteroaryl, (C₁-C₆)alkyl-SO₂—, formyl, —CN, (C₁-C₆)alkyl-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₁₀)heteroaryl-O—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—, (C₁-C₆)alkyl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—, phenyl-(C═O)—NH—,(C₁-C₁₀)heterocyclic-(C═O)—NH—, (C₁-C₁₀)heteroaryl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, (C₁-C₆)alkyl-SO₂NH—,(C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH—and (C₁-C₁₀)heteroaryl-SO₂NH—; wherein each of said phenyl andheteroaryl moieties may optionally be substituted by one or two radicalsindependently selected from the group consisting of halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino and [(C₁-C₆)alkyl]₂-amino.
 28. Acompound according to claim 1, wherein R⁷ is selected from the groupconsisting of R¹⁶—(C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)— and (C₃-C₁₀)cycloalkyl-NH—(C═O)—.
 29. Acompound according to claim 1, wherein R⁷ is selected from the groupconsisting of hydrogen and optionally substituted phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkyl.
 30. Acompound according to claim 1, wherein R⁷ is R¹⁴—(CR¹⁵H)_(p)—; p is oneto four; R¹⁴ is selected from the group consisting of hydrogen, halo,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, phenyl, (C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl,formyl, —CN, (C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, R¹⁶—(C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₁₀)heteroaryl-O—(C═O)—, H₂N—(C═O)—, R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heteroaryl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heterocyclic-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₃-C₁₀)cycloalkyl-[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy,R¹⁶—(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—,R¹⁶—(C₁-C₆)alkyl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, amino,R¹⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,phenyl-(C═O)—NH—, (C₁-C₁₀)heterocyclic-(C═O)—NH—,(C₁-C₁₀)heteroaryl-(C═O)—NH—,R¹⁶—(C₁-C₆)alkyl-(C═O)—[((C₁-C₈)alkyl)—N]—,phenyl-(C═O)—[(C₁-C₆)alkyl-N]—, R¹⁶—(C₁-C₆)alkyl-SO₂NH—,(C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH—and (C₁-C₁₀)heteroaryl-SO₂NH—; wherein each of the aforesaid phenyl,heterocyclic, heteroaryl or cycloalkyl R¹⁴ alternatives may optionallybe independently substituted by one to four moieties independentlyselected from the group consisting of halo, R¹⁶—(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,phenyl, benzyl, (C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl,(C₁-C₆)alkyl-SO₂—, formyl, —CN, R¹⁶—(C₁-C₆)alkyl-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, phenyl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₁₀)heteroaryl-O—(C═O)—, H₂N—(C═O)—, R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy,R¹⁶—(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—,R¹⁶—(C₁-C₆)alkyl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,R¹⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,phenyl-(C═O)—NH—, (C₁-C₁₀)heterocyclic-(C═O)—NH—,(C₁-C₁₀)heteroaryl-(C═O)—NH—,R¹⁶—(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, R¹⁶—(C₁-C₆)alkyl-SO₂NH—,(C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH—and (C₁-C₁₀)heteroaryl-SO₂NH—; wherein each of said phenyl andheteroaryl moiety alternatives may optionally be substituted by one ortwo radicals independently selected from the group consisting of halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino or[(C₁-C₆)alkyl]₂-amino; each R¹⁵ is independently selected from the groupconsisting of hydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,perhalo(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₈)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, formamidyl and (C₁-C₆)alkyl-(C═O)—NH—; and eachR¹⁶ is independently selected from the group consisting of hydrogen,halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,(C₁-C₆)alkyl-(C═O)—O—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, formamidyl and (C₁-C₆)alkyl-(C═O)—NH—.
 31. Acompound according to claim 1, wherein R⁷ is R¹⁴—(CR¹⁵H)_(p)—; p is oneto four; R¹⁴ is selected from the group consisting of hydrogen, halo,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₃-C₁₀)cycloalkyl, phenyl,(C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl, HO—(C═O)—,R¹⁶—(C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—, R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—,phenyl-NH—(C═O)—, (C₁-C₁₀)heterocyclic-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[N—((C₁-C₆)alkyl)]—(C═O)—, hydroxy,R¹⁶—(C₁-C₆)alkoxy, phenoxy, amino, R¹⁶—(C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino and R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—; wherein each ofthe aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R¹⁴alternatives may optionally be independently substituted by one to fourmoieties independently selected from the group consisting of halo,R¹⁶—(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,(C₁-C₆)alkyl-SO₂—, formyl, —CN, R¹⁶—(C₁-C₆)alkyl-(C═O)—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—, R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy, R¹⁶—(C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, R¹⁶—(C₁-C₆)alkyl-(C═O)—O—, amino,R¹⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—, R¹⁶—(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—and R¹⁶—(C₁-C₆)alkyl-SO₂NH—; each R¹⁵ is independently selected from thegroup consisting of hydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,perhalo(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, formamidyl and (C₁-C₆)alkyl-(C═O)—NH—; wherein nomore than two of said R¹⁵ groups may be other than hydrogen; and eachR¹⁶ is independently selected from the group consisting of hydrogen,halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,(C₁-C₆)alkyl-(C═O)—O—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, formamidyl and (C₁-C₆)alkyl-(C═O)—NH—.
 32. Acompound according to claim 1, wherein R⁵ is hydrogen.
 33. A compoundaccording to claim 1, wherein R⁵ is (C₁-C₁₀)heterocyclic or(C₁-C₁₀)heteroaryl; wherein each of the aforesaid heterocyclic andheteroaryl substituents may optionally be independently substituted byone to four moieties independently selected from the group consisting ofhalo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)— and [(C₁-C₆)alkyl]₂—N—(C═O)—.
 34. Acompound according to claim 1, wherein R⁵ is R¹⁴—(CHR¹⁵)_(p)—, p is 1-6;and R is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkenyl, perhalo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, phenyl,(C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl, phenyl-(S═O)—,(C₁-C₆)alkyl-SO₂—, phenyl-SO₂—, H₂N—SO₂—, (C₁-C₆)alkyl-NH—SO₂—,phenyl-NH—SO₂—, [(C₁-C₆)alkyl-]₂N—SO₂—, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O)—, R¹⁶—(C₁-C₆)alkyl-O—(C═O)—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₁₀)heterocyclic-O—(C═O)—,(C₁-C₁₀)heteroaryl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₁-C₁₀)heteroaryl-[N—(C₁-C₆)alkyl]-(C═O)—,(C₁-C₁₀)heterocyclic-[((C₁-C₆)alkyl)—N]—(C═O)—,(C₃-C₁₀)cycloalkyl[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy, R¹⁶—(C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—,R¹⁶—(C₁-C₆)alkyl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,R¹⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]2-amino, formamidyl,R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,phenyl-(C═O)—NH—, R¹⁶—(C₁-C₆)alkyl-SO₂NH—, (C₃-C₁₀)cycloalkyl-SO₂NH—,phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH— and(C₁-C₁₀)heteroaryl-SO₂NH—; wherein each of the aforesaid phenyl,heterocyclic, heteroaryl or cycloalkyl R¹⁴ alternatives may optionallybe independently substituted by one to four moieties independentlyselected from the group consisting of halo, R¹⁶—(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,phenyl, benzyl, (C₁-C₁₀)heterocyclic, (C₁-C₁₀)heteroaryl,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, formyl, —CN,R¹⁶—(C₁-C₆)alkyl-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—, phenyl-(C═O)—,(C₁-C₁₀)heterocyclic-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₁₀)heterocyclic-O—(C═O)—, (C₁-C₁₀)heteroaryl-O—(C═O)—, H₂N—(C═O)—,R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,phenyl-NH—(C═O)—, (C₁-C₁₀)heterocyclic-NH—(C═O)—,(C₁-C₁₀)heteroaryl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy, R¹⁶—(C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl-O—, phenoxy,(C₁-C₁₀)heterocyclic-O—, (C₁-C₁₀)heteroaryl-O—,R¹⁶-(C₁-C₆)alkyl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—,(C₁-C₁₀)heterocyclic-(C═O)—O—, (C₁-C₁₀)heteroaryl-(C═O)—O—, —NO₂, amino,R¹⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl,R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,phenyl-(C═O)—NH—, (C₁-C₁₀)heterocyclic-(C═O)—NH—,(C₁-C₁₀)heteroaryl-(C═O)—NH—,R¹⁶—(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—,phenyl-(C═O)—[(C₁-C₆)alkyl-N]—, R¹⁶—(C₁-C₆)alkyl-SO₂NH—,(C₃-C₁₀)cycloalkyl-SO₂NH—, phenyl-SO₂NH—, (C₁-C₁₀)heterocyclic-SO₂NH—and (C₁-C₁₀)heteroaryl-SO₂NH—; and wherein each of said phenyl andheteroaryl moiety alternatives may optionally be substituted by one ortwo radicals independently selected from halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino and [(C₁-C₆)alkyl]₂-amino.
 35. Acompound according to claim 1, wherein R⁵ is R¹⁴—(CHR¹⁵)_(p)—, p is 1-6;and R¹⁴ is selected from the group consisting of hydrogen, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₃-C₁₀)cycloalkyl, phenyl, (C₁-C₁₀)heterocyclic,(C₁-C₁₀)heteroaryl, HO—(C═O)—, R¹⁶—(C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—,R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—, phenyl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O), [(C₁-C₆)alkyl]₂—N—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, hydroxy, R¹⁶—(C₁-C₆)alkoxy, phenoxy,amino, R¹⁶—(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino,R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—; wherein each of the aforesaid phenyl,heterocyclic, heteroaryl or cycloalkyl R¹⁴ alternatives may optionallybe independently substituted by one to four moieties independentlyselected from the group consisting of halo, R¹⁶—(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, (C₁-C₆)alkyl-SO₂—,formyl, —CN, R¹⁶—(C₁-C₆)alkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,H₂N—(C═O)—, R¹⁶—(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,hydroxy, R¹⁶—(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,R¹⁶—(C₁-C₆)alkyl-(C═O)—O—, amino, R¹⁶—(C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, formamidyl, R¹⁶—(C₁-C₆)alkyl-(C═O)—NH—,R¹⁶—(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]— and R¹⁶—(C₁-C₆)alkyl-SO₂NH—;each R¹⁵ is independently selected from the group consisting ofhydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, perhalo(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl and(C₁-C₆)alkyl-(C═O)—NH—; wherein no more than two of said R¹⁵ groups maybe other than hydrogen; and each R¹⁶ is independently selected from thegroup consisting of hydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, hydroxy,(C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—O—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, formamidyl and(C₁-C₆)alkyl-(C═O)—NH—.
 36. A compound according to claim 1, wherein R⁶is hydrogen.
 37. A compound according to claim 1, wherein R⁶ isR⁹—B—(CH₂)_(n)— and n is zero.
 38. A compound according to claim 1,wherein R⁶ is R⁹—B—(CH₂)_(n)— and n is an integer from one to five. 39.A compound according to claim 1, wherein R⁶ is R⁹—B—(CH₂)_(n)—; n iszero; B is a bond and R⁹ is selected from the group consisting ofhydrogen, —CF₃, —C═N, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic or(C₃-C₁₀)cycloalkyl; wherein each of the aforesaid (C₁-C₁₀)heteroaryl,(C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkyl may optionally besubstituted by one to three moieties independently selected from thegroup consisting of halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkynyl,perhalo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,(C₁-C₆)alkyl-S—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—,(C₁-C₆)alkyl-(C≡O)—NH—, (C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN,(C₁-C₆)alkyl-(C═O)—, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)— and(C₁-C₆)alkyl-(C═O)—O—.
 40. A compound according to claim 1, wherein R⁶is R⁹—B—(CH₂)_(n)—; n is zero; B is —(C═O)—NR¹⁰—, —(R¹⁰—N)—,—(R¹⁰—N)—SO₂—, —(R¹⁰—N)—(C═O)—, >C═O, —O—(C═O)—, —SO₂—(NR¹⁰)—,—(R¹⁰—N)—(C═O)—(NR¹¹)—; and R⁹ is selected from the group consisting ofhydrogen, (C₃-C₁₀)cycloalkyl or phenyl; wherein the aforesaid phenyl and(C₃-C₁₀)cycloalkyl may optionally be substituted by one to threemoieties independently selected from the group consisting of halo,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, perhalo(C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[N(C₁-C₆)alkyl]-, —C N, (C₁-C₆)alkyl-(C═O)—,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)— (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)— and (C₁-C₆)alkyl-(C═O)—O—.
 41. A compoundaccording to claim 1, wherein R⁶ is R⁹—B—(CH₂)_(n)—; n is zero; B is—(C═O)—NR¹⁰—, —(R¹⁰—N)—, >C═O, —O—(C═O)—, —(R¹⁰—N)—(C═O)— or—(R¹⁰—N)—(C═O)—(NR¹¹)—; R⁹ is R¹³—(R¹²CH)_(m)—; m is 1-6; R¹⁰ ishydrogen or methyl; R¹² is hydrogen or methyl; and R¹³ is selected fromthe group consisting of hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-SO₂—NH—,phenyl-SO₂—NH—, (C₁-C₆)alkyl-SO₂—[N—(C₁-C₆)alkyl]-,phenyl-SO₂—[N—(C₁-C₆)alkyl]-, hydroxy, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, phenoxy, (C₁-C₁₀)heteroaryl-O—,(C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[N(C₁-C₆)alkyl]-, phenyl-(C═O)—NH—,phenyl-(C═O)—[N—(C₁-C₆)alkyl]-, —CN, (C₁-C₆)alkyl-(C═O)—, phenyl-(C═O)—,(C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[N—((C₁-C₆)alkyl)]—(C═O)—, (C₁-C₆)alkyl-(C═O)—O— andphenyl-(C═O)—O—.
 42. A compound according to claim 1, wherein R⁶ isR⁹—B—(CH₂)_(n)—; n is zero; B is —(R¹⁰—N)—; R⁹ is hydrogen orR¹³—(R¹²CH)_(m)—; m is 1-6; R¹⁰ is hydrogen or methyl; R¹² is hydrogenor methyl; and R¹³ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkyl.
 43. Acompound according to claim 1, wherein R⁶ is R⁹—B—(CH₂)_(n)—; n is oneto four; B is —(C═O)—NR¹⁰—, —(R¹⁰—N)—, —(R¹⁰—N)—(C═O)— or—(R¹⁰—N)—(C═O)—(NR¹¹)—; R⁹ is R¹³—(R¹²CH)_(m)—; m is 1-6; R¹⁰ ishydrogen or methyl; R¹² is hydrogen or methyl; and R¹³ is selected fromthe group consisting of hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, phenyl,(C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic, (C₃-C₁₀)cycloalkyl, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-SO₂—NH—,phenyl-SO₂—NH—, (C₁-C₆)alkyl-SO₂—[N—(C₁-C₆)alkyl]-,phenyl-SO₂—[N—(C₁-C₆)alkyl]-, hydroxy, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, phenoxy, (C₁-C₁₀)heteroaryl-O—,(C₁-C₁₀)heterocyclic-O—, (C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)— (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₆)alkyl-(C═O)—O— andphenyl-(C═O)—O—.
 44. A compound according to claim 1, wherein s is aninteger from zero to four and each R³ is independently selected from thegroup consisting of halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,perhalo(C₁-C₆)alkyl, phenyl, (C₁-C₁₀)heteroaryl, (C₁-C₁₀)heterocyclic,(C₃-C₁₀)cycloalkyl, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy,phenoxy, (C₁-C₁₀)heteroaryl-O—, (C₁-C₁₀)heterocyclic-O—,(C₃-C₁₀)cycloalkyl-O—, (C₁-C₆)alkyl-S, (C₁-C₆)alkyl-SO₂—,(C₁-C₆)alkyl-NH—SO₂—, —NO₂, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂-amino, (C₁-C₆)alkyl-SO₂—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—[((C₁-C₆)alkyl)—N]—, phenyl-(C═O)—NH—,phenyl-(C═O)—[((C₁-C₆)alkyl)—N]—, —CN, (C₁-C₆)alkyl-(C═O)—,phenyl-(C═O)—, (C₁-C₁₀)heteroaryl-(C═O)—, (C₁-C₁₀)heterocyclic-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—, HO—(C═O), (C₁-C₆)alkyl-O—(C═O)—, H₂N(C═O)—(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, phenyl-NH—(C═O)—,phenyl-[((C₁-C₆)alkyl)—N]—(C═O)—, (C₁-C₁₀)heteroaryl-NH—(C═O)—,(C₁-C₁₀)heterocyclic-NH—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)— and(C₁-C₆)alkyl-(C═O)—O—.
 45. A compound according to claim 1, wherein s isan integer from zero to four and each R³ is independently selected fromthe group consisting of halo, —CN, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl and perhalo(C₁-C₆)alkyl.
 46. A compound according toclaim 1, wherein s is an integer from zero to four and zero, one or twoof R³ are independently selected from the group consisting of halo,(C₁-C₆)alkyl, perhalo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino,—CN, and H₂N(C═O)—.
 47. A compound according to claim 1, wherein s is aninteger from zero to four and one of R³ is selected from the groupconsisting of optionally substituted phenyl, (C₁-C₁₀)heteroaryl,(C₁-C₁₀)heterocyclic and (C₃-C₁₀)cycloalkyl.
 48. A compound according toclaim 1, wherein s is an integer from zero to three and each R³ isindependently selected from the group consisting of halo, (C₁-C₆)alkyl,perhalo(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, perhalo(C₁-C₆)alkoxy, —NO₂,amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, —CN, and H₂N(C═O)—. 49.A compound according to claim 1, wherein s is an integer from zero totwo and each R³ is independently selected from the group consisting ofhalo, (C₁-C₆)alkyl, perhalo(C₁-C₆)alkyl, (C₁-C₆)alkoxy,perhalo(C₁-C₆)alkoxy and —CN.
 50. A compound according to claim 1,wherein s is an integer from zero to three and each R³ is independentlyselected from the group consisting of fluoro, chloro and methyl.